AU675730B2 - Substituted piperazinylcamphor derivatives as oxytocin antagonists - Google Patents
Substituted piperazinylcamphor derivatives as oxytocin antagonists Download PDFInfo
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- AU675730B2 AU675730B2 AU73292/94A AU7329294A AU675730B2 AU 675730 B2 AU675730 B2 AU 675730B2 AU 73292/94 A AU73292/94 A AU 73292/94A AU 7329294 A AU7329294 A AU 7329294A AU 675730 B2 AU675730 B2 AU 675730B2
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Description
WO 95/02587 PCT/US94/07769 -1- TITLE OF THE INVENTION SUBSTITUTED PIPERAZINYLCAMPHOR DERIVATIVES AS OXYTOCIN
ANTAGONISTS
FIELD OF THE INVENTION The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in obstetric and gynecologic therapy. The aforementioned pharmacologic activities are useful in the treatment of mammals. More specifically, the compounds of the present invention can be used in the treatment of preterm labor, stopping labor preparatory to Cesarean delivery, and in the treatment of dysmenorrhea. At the present time, there is a need in the area of obstetric and gynecologic therapy for such agents.
BACKGROUND OF THE INVENTION In the field of obstetrics, one of the most important problems is the management of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery, which is a leading cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances.
Tocolytic (uterine-relaxing) agents that are currently in use 2 include 32-adrenergic agonists, magnesium sulfate and ethanol.
Ritodrine, the leading 32-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant). Other p2-adrenergic agonists, including 3 terbutaline and albuterol have side effects similar to those of ritodrine.
Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired.
WO 95/02587 PCT/US94/07769 -2- Ethanol is as effective as ritodrine in preventing premature labor, but it doe, produce a corresponding reduction in the incidence of fetal resi ry distress that administration of ritodrine does.
It has been proposed that a selective oxytocin antagonist would be the ideal tocolytic agent. In the last few years, evidence has accumulated to strongly suggest that the hormone oxytocin is the physiological initiator of labor in several mammalian species including humans. Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium and in part by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may, in addition, be important in the cervical ripening process. By these mechanisms, the process of labor (term and preterm) is initiated by a heightened sensitivity of the uterus to oxytocin, resulting in part as a result of a well-documented increase in the number of oxytocin receptors in this tissue. This "up-regulation" of oxytocin receptors and enhanced uterine sensitivity appears to be due to trophic effects of rising plasma levels of estrogen towards term. By blocking oxytocin, one would block both the direct (contractile) and indirect (enhanced prostaglandin synthesis) effects of oxytocin on the uterus. A selective oxytocin blocker, or antagonist, would likely be more efficacious for treating preterm labor than current regimens. In addition, since oxytocin at term has major effects only on the uterus, such an oxytocin antagonizing compound would be expected to have few, if any, side effects.
The compounds of the present invention can also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antagonist can be more efficacious for treating dysmenorrhea then current regimens. An additional use for the present invention is for the stoppage of labor preparatory to Cesarean delivery.
WO 95/02587 PCT/US94/07769 -3- It is, therefore, a purpose of this invention to provide substances which more effectively antagonize the function of oxytocin in disease states in animals, preferably mammals, especially in humans. It is another purpose of this invention to prepare novel compounds which more selectively inhibit oxytocin. It is still another purpose of this invention to provide a method of antagonizing the functions of oxytocin in disease states in mammals. It is also a purpose of this invention to develop a method of preventing or treating oxytocin-related disorders of preterm labor and dysmenorrhea by antagonizing oxytocin.
It has now been found that compounds of the instant invention are antagonists of oxytocin and bind to the oxytocin receptor.
When the oxytocin receptor is bound by the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and thus being unable to exert its biologic or pharmacologic effects.
SThese compounds are useful in the treatment and prevention of oxytocin-related disorders of animals, preferably mammals and especially humans. These disorders are primarily preterm labor and dysmenorrhea. The compounds would also find usefulness for stoppage of labor preparatory to Cesarean delivery. Additionally, such 2 compounds are useful in inducing contraception in mammals inasmuch as oxytocin antagonists have now been shown to inhibit the release of oxytocin-stimulated luteinizing hormone (LH) by anterior pituitary cells.
Compounds of the present invention are also inhibitors of vasopressin and can bind to the vasopressin receptor. These compounds are useful in inducing vasodilation, treating hypertension, inducing diuresis and inhibiting platelet agglutination.
SUMMARY OF THE INVENTION The compounds and their pharmaceutically acceptable salts of the present invention are of the general formula
I
WO 95/02587 PCT/US94/07769 -4- R2/'X
(CH
2 )m N R R
R
5
R
e Y-
R
R
wherein a is a single or double bond; 1 5 W is Cor 0, provided that when W is O, then R 7 and R 8 are not present; Xis CH or
N;
Y is carbonyl, sulfonyl or
-CONH-;
Z is an optional substituent that, when present, is substituted or unsubstituted alkyl where said substituent is carboxyl;
R
I is hydrogen, unsubstituted or substituted alkyl where said substituent is halogen, WO 95/02587 PCT/US94/07769 halogen or alkoxy;
R
2 is hydrogen, unsubstituted or substituted alkyl where said substituent is halogen, halogen or alkoxy;
R
5 and R 6 are each independently selected from hydrogen, alkyl, phenylalkyl or oxo;
R
7 and R 8 are each independently selected from hydrogen, or alkyl, or
R
7 and R 8 together with W, when W is carbon, form a C3-6 carbocyclic ring;
R
9 and R 10 are together joined to form cyclic epoxide, whereby the R 9 and R 10 substituents are on the same carbon or on adjacent carbon atoms; or
R
9 and R10 are each independently selected from hydrogen, hydroxyl, halogen, oximido, methyl, carboxyl, WO 95/02587 PCT/US94/07769 -6carboxyalkyl, oxo, unsubstituted or substituted alkoxycarbonyl where said substituent is selected from pyridyl or piperidinyl, alkylcarbonyloxy, (11) alkylcarbonyloxyalkyl, (12) alkoxycarbonylalkoxy, (13) cyanoalkyl, (14) hydroxyalkyl, 0 (15) trihaloalkylsulfonyloxo, or (16) unsubstituted or substituted amino where said substituent is one or more of alkyl, carboxyalkyl or alkoxycarbonylalkyl; R 1, which is bonded to substituent Z when Z is present or which is bonded directly to the camphor ring when Z is not present, is hydrogen, oxo,
-N(R
12
)-CO-R
13 or -CO-N(R 1 4
R
12 is hydrogen, alkoxy, unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, hydroxyl, alkoxyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl, alkoxycarbonyl or alkoxycarbonylamino;
R
13 is hydrogen, alkoxyl, aralkoxyl, carboxyl, WO 95/02587 PCT/IJS94/07769 -7alkoxycarbonyl, alkoxycarbonylamino, unsubstituted or substituted cycioalkyl, wherein said substituent is carboxyl, unsubstituted or substituted phenyl wherein said substituent is one or more of carboxyl, carboxyalkyl or SO3H, unsubstituted or substituted amino, wherein said substituent is unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, alkylsulfonyl or unsubstituted membered heterocyclic rings having 1 or 2 heteroatoms, where said heteroatom is N, unsubstituted or substituted heterocyclic rings selected from the group consisting rf: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuiranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl and 1,1 -dioxotetrahydrothiopyranyl and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, alkylcarbonyl, carboxyl, carboxyalky carboxyaralkyl, aralkyl, aralkylcarbony1, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminoalkylcarbonyl, cyano, alkylsulfonyl, alkoxycarbonylaminoalkylcarbonyl, oxo or unsubstituted or substituted amino wherein said subsituent is one or more of alkyl, carboxylalkyl, alkoxycarbonyl or alkoxycarbonylalkyl or (11) unsubstitut(,d or substituted alkyl, wherein said substituent is one or more of hydroxyl, alkoxy, carboxyl, phenyl, hydroxypheny1, alkylphenyl, carboxyalkyiphenyl, cyano, alkylsulfonyl, acetamidino, formamidino, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, thio, alkylthio, alkoxycarbonyl, alkoxycarbonylalkyl, Ret, or unsubstituted or subtituted amino, wherein said substituent is one or more of alkyl, deuterated alkyl, WO 95/02587 WO 9502587PCT1/US94/07769 -8 piperidinyl, Cyc, pyridinyl, rnorpholhnyl, tetrahydropyranyl, tetrahydrothi apyrany I, tetrahydrothiapyranyl Soxide, alkoxycarbonylpiperidinyl, cyano, cyanoalkyl, hydroxyalkyl, haloalkyl, dialkyl, alkylcarbonyl, carboxyl, alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, aminoalkyl, aminocarbonyl, arninocarbonyl alkyl, alkylamninocarbonyl, phenalkyl or unsubstituted or substituted alkylcarboii,' where said substituent is a 5-membered heterocyclic ring having 1 or 2 heteroatoms and where said hetero atom is N, Cyc is defined as unsubstituted or substituted cycloalkyl wherein said substituent is alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolanyl and Het is defined as heterocyclic rings selected from the group con~sisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazo lyl, tetrahydrofuranyl, fuiranyl, dioxo lanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetrahydropyranyl, tetrahydrothiupyranyl, 1 -oxotetrahydrothiopyranyl and 201, 1 -dioxotetrahydrothiopyrary!': and wherein suid substituent for any of said heterocyclic rings are one or more of alkyl, amino, carboxyl, carboxyalkyl, aralkyl, carboxyaralkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alk,,xyalkoxyalkoxyalkyl, aralkylcarbonyl, aralkoxyalkyl, phenyl, aralkoxycarbonyl, oxo, SO3H, or unsubstituted or substituted amino wherein said substituent is E Ikyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl; WO 95/02587 PCT/US94/07769 -9-
R
14 and R 15 are each independently selected from hydrogen, unsubstituted or substituted alkyl where said substituent is one or more of hydrogen, carboxyl, amino, dialkylamino, aminoalkylamino, aminocarbonyl, hydroxyl, alkoxyl, alkylthio, thioalkyl, alk Isulfinyl, alkylsulfonyl, phenylalkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenalkyl or unsubstituted 5-membered saturated heterocyclic rings having 1 or 2 hetero atoms wherein said hetero atom is N or unsubstituted or substituted heterocyclic rings selected from the group consisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl and 1,1-dioxotetrahydrothiopyranyl and wherein said substituent is one or more of alkyl, oxo, carboxyl, phenylalkyl, carboxyphenylalkyl or alkoxycarbonvl; and m and n are integers of from 0 to 1; with the proviso that the bridging methylene moiety when n is equal to 1, or the moiety Y, when n is equal to 0, shall not be bonded to the camphor ring at either bridgehead position 3 or bridgehead position 6 unless Y is -CONH-.
In one embodiment are the compounds of the formula WO 95/02587 PCT/US94/07769
R%
,R
8 wherein Y is carbonyl or sulfonyl; 1 R 7 and R 8 are each independently selected from alkyl, or
R
7 and R 8 together with W, when W is carbon, form a C3-6 carbocyclic ring;
R
9 and R 10 (1) (2) (3) (4) (6) (7) (8) (9) (11) are each independently selected from hydrogen, hydroxyl, oximido, methyl, carboxyl, carboxyalkyl, unsubstituted or substituted alkoxycarbonyl where said substituent is selected from pyridyl or piperidinyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, cyanoalkyl, hydroxyalkyl or
I_~
WO 95/02587 PCT/US94/07769 11 (12) unsubstituted or substituted amino where said substituent is one or more of alkyl, carboxyalkyl or alkoxycarbonylalkyl; and R12is hydrogen or unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, hydroxyl, alkoxyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl.
In a class are the compounds of the formula In a class are the compounds of the formula wherein
R
9 and R 10 (1) (2) (3) (4) (6) (7) (8) (9) (11) are each independently selected from hydrogen, hydroxyl, oximido, methyl, carboxyl, carboxyalkyl, unsubstituted or substituted alkoxycarbonyl where said substituent is selected from pyridyl or piperidinyl, alkylcarbonyloxyalkyl, cyanoalkyl, hydroxyalkyl or unsubstituted amino; WO 95/02587 WO 9502587PCTIUS94/07769 12
R
13 is alkoxyl, unsubstituted or substituted heterocyclic rings selected from the group consisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl and 1,1 -dioxotetrahydrothiopyranyl and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, alkylcarbonyl, carboxyl, carboxyalcyl, carboxyaralkyl, aralkyl, aralkylcarbonyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminoalkylcarbonyl, cyano, alkylsulfonyl, alkoxycarbonylaminoalkylcarbonyl, oxo or unsubstituted or substituted ammno wherein said substituent is one or more of alkyl, carboxylalky 1, alkoxycarbonyl or alkoxycarbonyl alkyl or unsubstituted or substituted alkyl, wherein said substituent is one or more of hydroxyl, alkoxy, carboxyl, phenyl, hydroxyphenyl, alkyiphenyl, carboxyalkyiphenyl, cyano, alkcylsulfonyl, acetamidino, formamidino, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, thio, alkylthio, alkoxycarbonyl, aLkoxycarbonylalkyi, Het, or unsubstituted or substituted amino, wherein said substituent is one or more of alkyl, deuterated alkyl, piperidinyl, Cyc, pyridnyl, morpholinyl, tetrahydropyranyl, tetrahydrothiapyranyl, tetrahydrothiapyranyl Soxide, alkoxycarbonylpiperidinyl, cyano, cyanoalkyl, hydroxyalkyl, haloalkyl, dialkyl, alkylcarbonyl, carboxyl, alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, aloxycarbonylalkyl, aralkoxycarbonyl, amninoalkyl, amninocarbonyl, amino carbonylIalkyl1, alkylaminocarbonyl, phenalkyl or unsubstituted or substituted aikylcarbonyl, where said substituent is a 5-membered heterocyclic ring L WO 95/02587 PCT/US94/07769 13having I or 2 heteroatoms and where said hetero atom is N, Cyc is defined as unsubstituted or substituted cycloalkyl wherein said substituent is alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolanyl and Het is defined as heterocyclic rings selected from the group consisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl and 1,1 -dioxotetrahydrothiopyranyl; and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, amino, carboxyl, carboxyalkyl, aralkyl, carboxyaralkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl, aralkylcarbonyl, aralkoxyalkyl, phenyl, aralkoxycarbonyl, oxo, SO3H, or unsubstituted or substituted amino wherein said substituent is alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl; 15 are each independently selected from hydrogen or unsubstituted or substituted alkyl where said substituent is one or more of hydrogen, carboxyl, amino, dialkylamino, aminoalkylamino, aminocarbonyl, hydroxyl, alkoxyl, alkylthio, thioalkyl, alkylsulfinyl, alkylsulfonyl, phenylalkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenalkyl or unsubstituted 5-membered saturated heterocyclic rings having 1 or 2 hetero atoms wherein said hetero atom is N.
R
14 and R (1) (2) L I WO 95/02587 PCT/US94/07769 14- In a subclass are the compounds of the formula
R
7
R
8
R
11
A
N N Y R 1
CH
3 wherein
R
12 is hydrogen; and R1 4 and R 15 are each independently selected from hydrogen or unsubstituted or substituted alkyl where said substituent is one or more of dialkylamino, hydroxyl, alkylthio or thioalkyl.
Illustrative of the subclass are the compounds wherein Y is carbonyl; Rll is
-N(R
1 2
)-CO-R
1 3 or -CO-N(R 4 5; and R1 3 is hydrogen, alkoxyl, unsubstituted or substituted pyrrolidinyl wherein said substituent is alkoxycarbonylalkyl or (11) unsubstituted or substituted alkyl, wherein said substituent is one or more of hydroxyl, alkylsulfonyl, imidazolyl, or unsubstituted or substituted amino, wherein said substituent is one or more of tetrahydropyranyl or alkoxycarbonyl.
L -I WO 95/02587 PCT/US94/07769 15 Further illustrating this subclass are the compounds selected from the group consisting of O 0 -S
OH
H
2 N N
H
CH
3
H
2 N 0
HO
CH3
H
N N
CH
3
O
CH
3 and
CH
3
O
Exemplifying the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the instant invention.
More specifically illustrating the invention is a method of antagonizing the binding of oxytocin to its receptor binding site in a
I
WO 95/02587 PCT/US94/07769 16mammalian biologic system, comprising the step of introducing a pharmacologically effective amount of a compound of the instant invention into the mammalian biologic system.
Further illustrating the invention is a method of preventing preterm labor in a mammal in need thereof, comprising the step of administering to the mammal a pharmacologically effective amount of a compound of the instant invention.
A further illustration of the instant invention is a method of stopping labor prior to cesarian delivery in a mammal in need thereof, comprising the step of administering to the mammal a pharmacologically effective amount of a compound of the instant invention.
Specifically exemplifying the instant invention is a method of treating dysmenorrhea in a mammal in need thereof, comprising the step of administering to the mammal a pharmacologically effective amount of of the instant invention.
A further example of the invention is a method of antagonizing vasopressin from binding to its receptor site in a mammal, comprising the step of administering to the mammal a pharmacologically effective amount of a compound of the instant invention.
Another example is a method of inducing vasodilation in a mammal in need thereof, comprising the step of administering to the mammal a pharmacologically effective amount of a compound of the instant invention.
More particularly illustrating the instant ir vention is a method of treating hypertension in a mammal in need. ihereof, comprising the step of administering to the mamm a pharmacologically effective amount of a compov nd of the instant invention.
Another illustration of the invet',on is a method of inducing diuresis in a mammal in need thieeof, comprising the step of administering to the mammal a pharmac,:,ogically effective amount of a compound of the instant invention.
WO 95/02587 PCT/US94/07769 17 More particularly exemplifying the invention is a method of inhibiting platelet agglutination in a mammal in need thereof, comprising the step of administering to the mammal a pharmacologically effective amount of a compound of the instant invention.
A further exemplification of the invention is a method of causing contraception in a mammal in need thereof, comprising the step of administering to the mammal a pharmacologically effective amount of a compound of the instant invention.
A further illustration of the invention is a method of improving fertility rates in a farm animal, comprising the step of administering to the farm animal a pharmacologically effective amount of a compound of the instant invention.
The terms "bridgehead position 3 and bridgehead position 6 are with reference to the following numbering scheme of camphor-type bicyclic rings: 6 3 Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts: Acetate Lactobionate Benzenesulfonate Laurate Benzoate Malate Bicarbonate Maleate Bisulfate Mandelate WO 95/02587 PCT/US94/07769 18 Bitartrate Borate Bromide Calcium Edetate Camsylate Carbonate Chloride Clavulanate Citrate Dihydrochloride Edetate Edisylate Estolate Esylate Fumarate Gluceptate Gluconate Glutamate Glycollylarsanilate Hexylresorcinate Hydrabamine Hydrobromide Hydrochloride Hydroxynaphthoate Iodide Isothionate Lactate Mesylate Methylbromide Methylnitrate Methylsulfate Mucate Napsylate Nitrate N-methylglucamine ammonium salt Oleate Oxalate Pamoate (Embonate) Palmitate Pantothenate Phosphate/diphosphate Polygalacturonate Salicylate Stearate Sulfate Subacetate Succinate Tannate Tartrate Teoclate Tosylate Triethiodide Valerate The compounds of the present invention, may have 0 asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all WO 95/02587 PCT/US94/07769 19mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
The term "pharmacologically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this 1 range.
The term "alkenyl" shall mean straight or branched chain alkenes with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range.
The term "alkynyl" shall mean straight or branched chain alkyr.,s with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range.
The term "aryl" shall mean phenyl, naphthyl or fluorenyl.
The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms.
The term "trihaloalkylsulfonyloxo" shall mean the substituent 0
-O-S-CF
3
II
Whenever the terms "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent aralkoxyaryloxy) they shall be interpreted as including those limitations given above for "alkyl" and "aryl". Designated numbers of carbon atoms C WO 95/02587 ICT/US94/07769 shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The term "oxo" shall refer to the substituent =0.
The term "halogen" shall include iodine, bromine, chlorine and fluorine.
The term "preterm labor" shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.
The term "dysmenorrhea" shall mean painful menstruation.
The term "cesarean delivery" shall mean incision through the abdominal and uterine walls for delivery of a fetus.
The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent.
Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
The ability of the compounds of the instant invention to antagonize oxytocin makes these compounds useful as pharmacologic agents for mammals, especially for humans, for t' treatment and prevention of disorders wherein oxytocin may be involved. Examples of such disorders include preterm labor and especially dysmenorrhea.
These compounds may also find usefulness for stoppage of labor preparatory to Cesarean delivery.
The compounds of the present invention also bind to the vasopressin receptor and are therefore useful as vasopressin antagonists.
Vasopressin antagonists are useful in the treatment or prve.ntion of disease states involving vasopressin disorders, including their use as diuretics and their use in congestive heart failure.
In addition, the compounds of the instant invention are useful for improving fertility rates in farm animals. In certain farm WO 95/02587 PCT/US94/07769 -21 animals (sheep, cattle, swinc, goats), the secretion of oxytocin from the ovary and/or pituitary acts on the uterine endometrium to stimulate the secretion of prostaglandins which in turn, causes the regression of the corpus lutoum of the ovary. In the cycling animal, destruction of the corpus luteum removes the source of progesterone that is key to the preparation of the uterus for pregnancy. In the animal where fertilization has occurred, the conceptus secrete a factor that antagonizes the action of oxytocin to induce luteolysis, resulting in the continued secretion of progesterone. The maintenance of a functioning corpus luteum is obligatory to the initiation of pregnancy. An oxytocin antagonist given at this critical period supplements the natural signal from the conceptus to prolong corpus luteal function. The result is to increase pregnancy rates by enhancing the chances of impregnation through a reduction in embryonic loss.
The compoundP of the present invention can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions.
Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
An effective but non-toxic amount of the compound desired can be employed as a tocolytic agent.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.3-6.0 gm/day orally.
I WO 95/02587 PCTIUS94/07769 -22- Intravenously, the most preferred doses will range from 0.1 to about mg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of 'wo, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throug 'out the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, zanthan gum and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small WO 95/02587 PCT/US94/07769 -23 unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are. coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
The compounds of the present invention can be prepared readily according to the following reaction Schemes and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.
WO 95/02587 WO 9502587PCT/IJS94/07769 24 SCHEME I
H
Where W is a suitable leaving group cI-Y WO 95/02587 WO 9502587PCT[IUS94/07769 25 ISCHEME 2 1) NaH
I
2) R 7 -I4 SCHEME 3 R 3 R 2
NH
2 0H
I\
Ra-Ni
H
2 WO 95/02587 WO 9502587PCTJUS94/07769 26 SCHEME 4 R 3 Hq 2
Z//R
N"-
RH
4
H
5 N -t0
RH
6 68 SCHEME LiOH
NH
R
8
BOP
PCT/US94/07769 WO 95/02587 27 SCHEME 6
DPPA
t-bUtanol WO 95/02587 PCTIUS94/07769 28 SCHEME 7 (CH2R
I
R
5 W W R 6
N
H
Where W is a suitable leaving group WO 95/02587 WO 9502587PCT/US941'07769 29 SCHEME 8 0 1CH 2
-S-(H
3 2 2) H-NR 2 SCHEME 9 1)Me 3
-SH--CN
2) LAH 3) RN rCI 0 0 WO 95/02587 WO 95/2587 CT/US94/07769 30 SCHEME 1)H 2 CCHMgBr S012
H-NR
2 SCHEME 11 3> 1) 00) 2) Pd C0; MeOH 3) NaOH 4) BOP, H-NR 2
/R
N 1 R 6 0- 0
NR
2 WO 95/02587 WO 9502587PCI'/US94/07769 31 SCHEME 12 Li R' N
LAH
OH 0 N4 SCHEME 13 1) NH 2 0H 2) H 2 Raney Nickel R 'kCl
R
R6 01 H N WO 95/02587 WO 9502587PCT/US94/07769 32 SCHEME 14 7 0\ ~CF3- )o0 2) Pd CC 3) Sm 12, THF,, M.-tH 4) NaOH BOP, H-NR 2
CONR
2 Abbreviations used in the Examples are as follows: TEA triethylamine DLEA dilsopropylethylamine BOP benzotriazolylIoxytri s(dimethylIamino) phosphonium, hexafluorophosphate THE tetrahydrofuran DMF dimethylformamide LAH lithium aluminum hydride TFA trifluoroacetic acid HPLC Method A 15 min. linear gradient 95:5 A:B to 0:100 A:B A H20 containing 0. 1% by vol. TEA B CH3CN containing 0. 1% by vol. TFA mE/mmn flow rate 12 cm Cl18 reverse phase column UV detection (215 nm) TLC was performed on 20 cm plates coated with silica gel (250 microns) from Analtech.
WO 95/02587 PCT/US94/07769 -33 EXAMPLE 1 1-(2-methylphenyl)-4-[(4,7,7-trimethyl-3-oxobicyclo[2.2.1 ]hept-2endo-vl)carbonyl-piperazine and 1-(2-methylphenyl)-4-[(4,7,7-trimethyl-3-oxobicyclo[2.2.1 ]hept-2exo-yl)carbonyl]-piperazine
OH
3 aN O 0
N
0 To a solution of camphor-a-carboxylic acid (200 mg, 1.02 mmol) in methylene chloride (50 mL) at 0 0 C was added oxallyl chloride (0.098 mL, 1.1 followed by dimethyl formamide (2 drops). After warming to room temp., and stirring for 1.5 h the solution was concentrated. The residue was redissolved in methylene chloride (50 mL) and o-tolyl piperazine hydrochloride (239 mg, 1.12 mmol) was added, followed by N-methylmorpholine (0.224 mL, 2.04 mmol). After stirring at room temperature for 4 h, the mixture was concentrated, then partitioned between ethyl acetate and water (100 mL of each). The ethyl acetate layer was dried over sodium sulfate, then concentrated. The residue was passed through a silica gel column using 30% ethyl acetate in petroleum ether as eluant. Crystallization from methylene chloride/petroleum ether afforded pure endo isomer as fine needles (173 mg). The exo isomer was obtained as a white solid from concentration of the mother liquor (62 mg).
The 2-endo and 2-exo diastereomers derived from camphor-a-carboxylic acid were also prepared in the same way.
i-- WO 95/02587 WO 95/2587 CT/US94/07769 34 Analytical data for the 2-endo and 2-exo compounds in the camphor series was identical to that shown for the corresponding isomers in the series.
Exo isomer: TLC: Rf (15% ethyl acetate in hexane) 0.30 Analysis: (C22H30N202) calc. C, 74.54; N, 7.90; H, 8.53 found C, 74.29, N, 7.55; H, 8.88 HPLC: (method A) Rt 12. 10 min.
FABMS: mlz 355 H) I'H NMR: consistent with structure.
Endo isomer: TLC: Rf (15% ethyl acetate in hexane) =0.09 185-187'C Analysis: (C221-30N202) caic. C, 74.54; N, 7.90; H, 8.53 found C, 74.42; N, 7.79; H, 8.67 HPLC: (method A) Rt 11.73 min.
FABMS: m/z 355 H) 1 H NMR: consistent with structure.
EXAMPLE 2 I -I(3-hydroxy-4,7,7-trimethylbicyclol2.2.1 Ji ept-2-yl)carbonyl]-4-(2methvlphenyl)-vinerazine WO 95/02587 PCT/US94/07769 To a solution of 1-(2-Methylphenyl)-4-[(4,7,7-trimethyl-3oxobicyclo[2.2.1 ]hept-2-endo-yl)carbonyl]-piperazine (50 mg, 0.141 mmol) in methanol (15 mL) was added, while stirring rapidly, small scoops of sodium borohydride. When the reaction was complete, as judged by TLC, the mixture was concentrated, then partitioned between ethyl acetate and water (25 mL of each). The aqueous layer was washed 2 X 10 mL with ethyl acetate, then the combined ethyl acetate extracts were dried over sodium sulfate and concentrated. The title compound was purified by silica gel chromatography (15% ethyl acetate in petroleum ether as eluant) to yield 42 mg of white powder.
Analysis: (C22H32N202) calc. C, 74.12; H, 9.05; N, 7.86 found C, 74.07; H, 9.39; N, 7.76 HPLC: (method A) Rt 11.05 min.
FABMS: m/z 357 H) 1 H NMR: consistent with structure.
EXAMPLE 3 1 -(2-methylphenyl)-4-[(2,4,7,7-tetramethyl-3-oxo bicyclo[2.2.1 ]hept-2yl)carbonyll-piperazine
CH,
3
N
CH
3
O
To a solution of l-(2-Methylphenyl)-4-[(4,7,7-trimethyl-3oxobicyclo[2.2.1 ]hept-2-endo-yl)carbonyl]-piperazine (50 mg, 0.141 mmol) in tetrahydrofuran (25 mL) was added sodium hydride dispersion in oil, 7 mg, 0.169 mmol), followed by methyl iodide (0.044 _1_ WO 95/02587 PCT/US94/07769 -36mL, 0.705 mmol). After 5 h, additional sodium hydride was added (3 mg). After 3 days, the mixture was concentrated, then partitioned between ethyl acetate and water (25 mL of each). The ethyl acetate layer was dried over sodium sulfate then concentrated. Purification by silica gel chromatography (10% ethyl acetate in petroleum ether as eluant) afforded 42 mg of the title compound as a clear film.
TLC: Rf (20% ethyl acetate in hexanes) 0.62 HPLC: (method A) Rt 12.70 min.
FABMS: m/z 369 H) 1 H NMR: consistent with structure.
EXAMPLE 4 1 -(2-methylphenyl)-4-[(4,7,7-trimethyl-3-oxo-2-carboxymethylbicyclor2.2.1 Ihept-2-yl)carbonyll-piperazine
CH
3
O
N
N
0 CO2" To a solution of 1-(2-Methylphenyl)-4-[(4,7,7-trimethyl-3oxobicyclo[2.2.1 ]hept-2-endo-yl)carbonyl]-piperazine (341 mg, 0.962 mmol) in tetrahydrofuran (50 mL) was added sodium hydride dispersion in oil, 58 mg, 1.44 mmol), followed by 2-iodoethyl acetate (0.228 mL, 1.92 mmol). After stirring at room temperature for 18 h, the mixture was concentrated to afford the ethyl ester intermediate.
To a solution of the ester (150 mg, 0.352 rnmol) in methanol (50 mL) was added 1 M sodium hydroxide (0.703 mL, 0.703 mmol). The solution was warmed to 50°C. After 2 h the mixture was concentrated, then partitioned between ethyl acetate and 1 M HCI (100
~CI~I~
WO 95/02587 PCT/US94/07769 -37 mL of each). The ethyl acetate layer was dried over sodium sulfate, then concentrated. The title compound was purified by silica gel chromatography methanol in methylene chloride as eluant).
TLC: Rf methanol in methylene chloride) 0.24 Analysis: (C23H30N204) 0.15 ethyl acetate calc. C, 69.40; H, 7.86; N, 6.58 found C, 69.46; H, 7.84; N, 6.23 HPLC: (method A) Rt 11.23 min.
FABMS: m/z 413 H) 1H NMR: consistent with structure.
EXAMPLE 1-(2-methylphenyl)-4-[(4,7,7-trimethyl-3-oxo-2-cyanomethylbicyclor2.2.1 hept-2-yl)carbonyll-piperazine C O
NCN
O
CN
To a solution of 1-(2-Methylphenyl)-4-[(4,7,7-trimethyl-3oxobicyclo[2.2.1 ]hept-2-endo-yl)carbonyl]-piperazine (316 mg, 0.891 mmol) in tetrahydrofuran (50 mL) was added sodium hydride dispersion in oil, 54 mg, 1.34 mmol), followed by 2-iodoacetonitrile (0.129 mL, 1.78 mmol). After stirring at room temperature for 18 h, the mixture was concentrated. The title compound was purified by silica gel chromatography (15% ethyl acetate in petroleum ether as eluant).
WO 95/02587 PCT/US94/07769 -38 TLC: Rf (10% ethyl acetate in petroleum ether) 0.26 Analysis: (C24H31N302) 0.34 ethyl ether calc. C, 72.74; H, 8.28; N, 10.04 found C, 72.67; H, 7.99; N, 10.03 HPLC: (method A) Rt 12.8 min.
FABMS: m/z H) 1 H NMR: consistent with structure.
EXAMPLE 6 1-(2-methylphenyl)-4-[(4,7,7-trimethyl-3-hydroxyimino-bicyclo[2.2.1]hept-2-endo-vl)carbonyll-piperazine 1 5 C HH O(N
HON
N
O
To a solution of 1-(2-Methylphenyl)-4-[(4,7,7-trimethyl-3oxobicyclo[2.2.1]hept-2-exo-yl)carbonyl]-piperazine (750 mg, 2.1 mmol) in pyridine (30 mL) was added hydroxylamine hydrochloride (300 mg, 8.57 mmol), then the temperature was increased to 70 0
C.
When the starting material had disappeared from the TLC, the mixture was concentrated. Silica gel chromatography (96:4:0.4 chloroform: methanol: ammonia as eluant) afforded the title compound as a white solid.
Analysis: (C22H32N302) 0.30 chloroform 0.25 methanol calc. C, 65.36; H, 8.10; N, 10.14 found C, 65.38; H, 7.83; N, 9.80 WO 95/02587 WO 9502587PCT/US94/07769 39 HPLC: (method A) Rt 10.46 min.
FABMS: m/z 371 +H) IH NMIR: consistent with structure.
EXAMPLE 7 1 -(2-methylphenyl)-4-[(4,7,7-trimethyl-3-exo-aninobicyclo[2.2. 1 ]hept- 2-endo-yl)carbonyl] -p2iperazine and 1 -(2-methylphenyl)-4-[(4,7 ,7-trimethyl-3-endo-aminobicyclo [2.2.1 I he~t- 2-endo -y1) carbon v]1 -piperazine
OH
3 O(N ")H 2
N
0 To a solution of 1-(2-miethylphenyl)-4-[(4,7,7-trimnethyl-3hydroxyimino-bicyclo[2.2. 1]hept-2-endo-y l)carbonyl] -piperazine (3 g, 2.29 mmol) in 2-methoxyethanol (100 mL) was added freshly prepared Raney-nickel (8-10 g of the Ra-Ni/ethanol slurry), then the reaction vessel was placed under hydrogen atmosphere (60 psi) on a Parr hydrogenator. After 2 days, the mixture was filtered. Purification by flash chromatography (98:2:0.2 chloroform: methanol: ammonium hydroxide as eluant) yielded endo and exo reduction product amines.
TLC: Rf (95:5:0.5 chloroform:methanol: ammonium hydroxide)= r '0.
Analysis: (C22H33N301) 0.1 ethyl acetate WO 95/02587 PCT/US94/07769 calc. C, 73.84; H, 9.35; N, 11.53 found C, 73.88; H, 9.23; N, 11.60 HPLC: (method A) Rt 9.39 min.
FABMS: m/z 356 H) 1H NMR: consistent with the structure.
FLC: Rf (95:5:0.5 chloroform:methanol:ammonium hydroxide)= 0.42 Analysis: (C22H33N301) 0.2 chloroform calc. C, 70.27; H, 8.82; N, 11.08 found C, 70.44; H, 9.22; N, 11.07 HPLC: (method A) Rt 10.12 min.
FABMS: m/z 356 H) 1H NMR: consistent with the structure.
EXAMPLE 8 General Coupling Procedure: For coupling carboxylic acids with the amine products of Example 7: To the amine (400 mg, 1.17 mmol) in dimethylformamide (6 mL) was added the carboxylic acid component (1.4 mmol) and Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 619 mg, 1.4 mmol). Triethylamine was added to adjust the pH to 8. After stirring at room temperature for 18 h, the mixture was concentrated, then partitioned between ethyl acetate ard 1 M aqueous sodium hydroxide (75 mL of each). The ethyl acetate solution was washed with 1 M HCI, and brine, then dried over sodium sulfate and concentrated. The products were obtained by flash chromatography.
WO 95/02587 WO 9502587ITVUS94/07769 -41 EXAMPLE 9 1 -(2-methylphenyl)-4-[(4,7 ,7 -trimethyl-3 -exo-(4-methylsu Ifonyl-2-tbutox ycarbonyl amino) butanoylamnino bicyclo[2.2. 1 ]hept-2-endoycarbonyll-p2iierazine 0 0 0 0 BocHN N
H
~H
N N: 0
OH
3 0 The title compound was prepared from I -(2-methylphenyl)-4-[(4,7,7-trimethyl-3-exo-aminobicyclo[2.2. 1 Ihept-2-endoyI)car',ony1]-piperazine and N-Boc methionirie sulfone according to the General Coupling Procedure.
TLC: Rf (95:5:0.5 chloroform:methanol: ammonium hydroxide) 0.37 Analysis: (C32H50N406S 1) 0.25 chloroform 0.50 ethyl acetate caic. C, 59.38; H, 7.89; N, 8.09 found C, 59.47; H, 8.16; N, 8.07 HPLC: (method A) Rt 12.58 min.
FABMS: m/z 619 H) IH NMR: consistent with the structure.
WO 95/02587 WO 9502587PCT/US94/07769 42 EXAMPLE 1 -(2-methylphenyl)-4-[(4,7,7-trimethyl-3-exo-(4-methylsulfonyl-2amino) butanoylamnino bicyclo[2.2. 1 ]hept-2-endo-yl)carbonv1J piperazine 0 0 100
H
2 N N
H
~H
N N0
OH
3 0 To a solution of I -(2-methy iphenyl 1(4,7,7 -trimethyl-3exo-(4-methylIsu lfonyl -2-t-butoxycarbonyl amino) -butanoylarnin o bicyclo[2.2.lIflhept-2-yl)carboniyll-piperazine in ethyl acetate at 0 0 C was introduced HCl gas. After 3 h, the mixture was concentrated. The title compound was purified by preparative HPLC (95:5 to 5:95 acetonitrile: water with 0. 1% TFA) to yield 200 mg of the TFA salt.
TLC: Rf (95:5:0.5 chloroform:methano1: ammonium hydroxide)= 0.11 96 97'C Analysis: (C27H42N404S 1) 2.05 TFA 0.7 water caic. C, 48.82; H, 5.99; N, 7.32 found C, 48.82; H, 6.01; N, 7.54 HPLC: (method A) Rt =9.94 min.
FAB MS: m/z =519 +H) IH NMR: consistent with the structure.
WO 95/02587 WO 9502587PCT/US94107 769 43 EXAMPLE I1I I -(2-methylphenyl)-4-[(4,7 ,7-trimethyl-3 -endo-(4-methylsulfonyl-2-tbu tox ycarbonyl amino) butanoylamino bicyclo [2.2.1 ]hept-2-endo-yl)carbonvyI l-pip1erazine o o
HN
~~N~NH
CH
3 The title compound was prepared from 1-(2-methylphenyl)-4-Ii(4,7 ,7-trimethyl-3-endo-aminobicyclo[2.2. 1 ]hept-2-endoyl)carbonyljl-piperazine and N-Boc methionine sulfone according to the General Coupling Procedure.
Analysis: (C32H50N40(6 0.5 CHCI3 caic. C, 57.52; i, 7.50; N, 8.26 found C, 57.54; H, 7.72; N,8.02 HPLC: (method A) Rt 13.44 min.
FABMS: mlz 619 H) IH NMR: consistent with the structure.
WO 95/02587 WO 9502587PCT/US94/07769 44 EXAMPLE 12 I -(2-methyiphenyl)-4-[(4,7 ,7-trimethyl-3-endo-(4-methylsulfonyl-2amino) butanoylamnino bicyclolj2.2. 1]hept-2-endo-ylcarbonyl]piperazine -0 0 100
N\
2 N
N
OH
3 0 The title compound was prepared from 1-(2-methylphenyl)-4- ,7-trimethyl-3 -endo-(4-methylsulfonyl-2-t-bu toxycarbonylamnino) butanoylamino bicyclo[2.2.1I]hept-2-endo-yl)carbonyl]piperazine by an route analogous to that described for 1 -(2-methylphenyl)-4- ,7-trimethyl-3 -exo-(4-methylsulfonyl-2-amino)butanoylamnino bicyclo [2.2.1 ]hept-2-endo-yI)carbonyl 1-piperazine.
Analysis: (C27H42N404S 1) 2.15 water caic. C, 58.17; H, 8.37; N, 9.76 found C, 58.16; H, 8.16; N, 10.05 HPLC: (method A) Rt 10.58 min.
FAB MS: m/z =519 +H) IH NMR: consistent with the structure.
WO 95/02587 WO 9502587PCI'/US94/07769 45 EXAMPLE 13 1 -(2-Methylphenyl)-4-[(4,7,7-trimethyl-3-(2-(4-imidazolyl)) acetylamino bicyclor2.2. I]hept-2-v!).parbonvl 1-piperazine
CH
3 0 The title compound was prepared from 1 -(2-methylphenyl )4-I(4 ,7,7-trimnethyl-3-aminobicyclo [2.2.1 ]hept-2-yl)carbonyl]Ipiperazine and imidazole acetic acid according to the General Coupling Procedure.
TLC: Rf (90:10:1 chloroform: methanol: ammonium hydroxide) 0.41 Analysis: (C27H37N502) 1.0 ethyl acetate 0.05 chloroform caic. C, 66.87; H, 8.14; N, 12.56 found C, 66.99; H, 8.19; N, 12.55 HPLC: (method A) Rt 10. 19 min.
FABMS: m/z 464 H) III NMR: consistent with the structure.
WO 95/Q25007 WO 9SQ2~7PCT/US94/07769 46 EXAMPLE 14 1 -(2-methylphenyl)-4-[(4,7,7-trirnethyl-3-acetylamino bicyclo-[2.2. 1]heipt-2-vilcarbonvil-DiDerazine
N.
H
CH
3 0 To a solution of 1 -(2-methylphenyl)-4- [(4,7,7-trimethyl-3aminobicyclo[2.2.l1 hept-2-yl)carbonyl] -piperazine (50 mg, 0.14 mmnol) in niehylene chloride (3 mL) w,,s added acetic anhydride (0.016 mL, 0.169 mmol) followed by 4-dimethylaminopyridine (DMAP, 21 mg, 0.169 mmol). After 3 h, the mixture was concentrated, then partitioned between ethyl acetate and 10% aqueous citrate (25 mL each). The ethyl acetate layer was then washed with brine, dried over magnesium sulfate and concentrated. The title compound was purified by preparative TLC (3 X 0.25 mm plates, 96:4:0.4 chiloroformn:rnethanol:arnmonium hydroxide as eluant) TLC: Rf (95:5:0.5 chloroform:methanol:ammonium hydroxide) 0.39 Analysis: (724H35N302) 0.8 water calc. C, 69.85; H, 8.52:, N, 10.18 found C, 69.92; H, 80.4 1; N,10. 12 HPLC: (method A) Rt 11.82 min.
FABMS: m/z 398 Ii) IH NMR: consistent with the structure.
WO 95/02587 WO 9502587PCI'/US94/07769 47 EXAMPLE 1 -(2-methy lphenyl)-4- 4,7,7 -trimeth yI- 3 -prolIyl amino bicyclo-[2.2. 1]hept-2-yl )carbonvil -piperazine H 0 N
L
CH
3 N-Boc Proline was coupled to I -(2-methylphenyl)-4- -trimethyl-3-aminobicyc lo [2.2.1 ]hept-2-y l)carbonyl] -piperazine using BOP reagent as described in the General Coupling Procedure.
The Boc protected intermediate was dissolved in ethyl acetate and cooled to 0 0 C. HC1 gas was introduced. After 5 h, the mixture was concentrated. The title compound was purified by preparative HPLC (90: 10 to 10:90 water:acetonitrile 0. 1% TFA as eluant).
TLC: Rf (95:5:0.5 chloroform:methianol :amfmonium hydroxide) 0.46 Analysis: (C27H40N402) 0.55 water 2.0 TFA calc. C, 53.9 1; H, 6.29; N, 8.11 found C, 53.92; H, 6.27; N, 8. 19 HPLC: (method A) Rt 9.88 min.
FABMS: mlz 453 H) IH NMR: consistent with the structure.
WO 95/02587 PCTfUS94/07769 -48 EXAMPLE 16 1-(2-methylphenyl)-4-[(4,7,7-trimethyl-3-(I -(ethoxycarbonylethyl)prolyl amino bicvclor2.2. hept-2-yl)carbonvll-piperazine EtO2C 0
N
H
1 0 Nir N
CH
3 0 To a solution of 1-(2-methylphenyl)-4-[(4,7,7-trimethyl-3prolyl amino bicyclo[2.2.1]hept-2-yl)carbonyl]-piperazine (100 mg, 0.221 mmol) in methanol (3 mL) was added ethyl acrylate (0.024 mL, 0.221 mmol) and triethylamine (0.045 mL, 0.44 mmol). After stirring at room temperature for 18 h, the mixture was concentrated, then partitioned between ethyl acetate and sat'd sodium bicarbonate (50 mL each). The ethyl acetate was washed with brine, then dried over magnesium sulfate and concentrated. The title compound was purified by preparative TLC (3 X 0.5 mm plates, 96:4:0.4 chloroform: methanol:ammonium hydroxide as eluant) to yield a 70:30 mixture of ethyl:methyl esters.
TLC: Rf (95:5:0.5 chloroform:methanol:ammonium hydroxide) 0.35 Analysis: (C32H48N404) 0.15 methanol 0.20 chloroform calc. C, 66.68; H, 8.42; N, 9.71 found C, 66,63; H, 8.42; N,10.40 HPLC: (method A) Rt 10.77 min (methyl ester), 11.15 min (ethyl ester) FABMS: m/z 539 H, methyl ester), 553 H, ethyl ester) 1 H NMR: consistent with 70:30 ratio of ethyl:methyl esters.
WO 95/02587 WO 9502587PCT/IJS9',t,7769 49 EXAMPLE 17 I -(2-methyiphenyl -trimethyl-3-(2-hydroxy-2, 2dimethyV)acetvlaminobicyclo[2.2. I hept-2-v I)carbonyl 1-piperazine HC>~4H
NN
OH
3 0 2-hydroxy isobutyric acid was coupled to 1-(2-methylphenyl)-4-[(4 ,7 ,7-trimethyl-3-aminobicyclo [2.2.1 ]hept-2-yl)carbonyl] piperazine using BOP reagent as described in the Gev raI Coupling Procedure. The title compound was purified by flash chromatography (2:1 hexanes:ethyl acetate as eluant).
TLC: Rf (2:3 ethyl acetate:hexanes) 0.38 Analysis: (C26H-19N303) 0.4 chloroform 0.65 ethyl acetate caic. C, 63.71; H, 8.22; N, 7.69 found C, 63.71; H, 8.19; N, 7.82 HPLC: (method A) Rt 11.59 min.
FABMS: mlz 442 H) IH NMR: consistent with the structure.
WO 95/02587 WO 9502587PCT/1US94/07769 50 EXAMPLE 18 I -(2-methylphenyl)-4-(4 ,7 ,7 -trimethyl -3 -(2,,3-dihydroxy) propionyl aminobicyclo[2.2. I lhept-2-vJ )carbonvfl-p2iperazine 0
HO
HO
CH
3 Glyceric acid was coupled to 1 -(2-methylphenyl)-4-i(4,7,7trimethyl-3-exo-arniinobicyclo 12.2.1 Ihept-2-endo-yl)carbonyl] piperazine using BOP reagent as described in the Generai Coupling Procedure. The title compound w.-s purified by preparative TLC (2 X mm plates, 92:8:0.8 chloroform:methanol: ammonium hydroxide as eluant).
TLC: Rf ,5:5:0.5 chloroform:methanol:ammonitm hydroxide) 0.28 Analysis: (C25H37N304) 0.1 chloroform 0. 1 methanol calc. C, 65.98; H, 8.24; N, 9.16 found C, 65.95; H, 8.39; N,9.21 HPLC: (method A) Rt 10.63 min.
FABMS: m/z 434 H) I-i NMR: consistent with the structure.
WO 95/02587 WO 9502587PCT/US94/07769 51 EXAMPLE 19 I -(2-methylphenyl)-4-[(4,7,7-trimethyl-3-(2-(t-butoxycarbonyl)amino- 3-hydroxy) butvrvl aminobicyclo[2.2. Ilhept-2-vl)carbonvlil-uiperazine BocHN 0
HO
OH
3
F
OH
3 N-Boc threonine was coupled to I -(2-methylphenyl)-4- -trimethyl -3-ex.o-aminobicyclo [2.2.1 ]hept-2-endo-yl)carbonyllpiperazine using BOP reagent as described in the General Coupling Procedure. The title compound was purified by flash chromatography (2:1 ethyl acetat:hexanes as eluant).
TLC: Rf (95:5:0.5 chloroformn:methanol:ammonium. hydroxide) 0.41 Analysis: (C31H48N405) 0.25 chloroform caic. C, 63.98; H, 8.29; N, 9.55 found C, 64.05; H, 8.33; N, 9.83 HPLC: (method A) Rt 13.07 min.
FABMS: mlz 557 H) IIH NMR: consistent with the structure.
WO 95/02587 WO 9502587PCTIUS94/07769 52 EXAMPLE 1 -(2-methylphenyl)-4-[(4,7,7-trimethyl-3 .(2-amino-3-hydroxy)butyryl aminobicvclor2.2.l1 hept-2-yl)carbonvl1-piperazine
H
2 N 0
HO
OH
3 H N N
OH
3 0 To a solution of l-(2-methylphenyl)-4-[(4,7,7 -trimethyl-3- (2-(t-butoxycarbonyl)amino-3 -hydroxy) butyryl aminobicyclo hept-2-yl)carbonyl]-piperazine (30 mg, 0.059 mmol) in ethlv acetate mL) at 0 0 C was introduced a stream of HCI gas. After 2 h, the mixture was filtered, then the filtrate was dried under high vac. to yield 25 mg.
Analysis: (C31I H40N403) 0.36 ethyl acetate calc. C, 51.24; H, 7.39; N, 8.72 found C, 51.20; H, 7.28; N, 8.68 HPLC: (method A) Rt 10.29 min.
FABMS: m/z 457 H) IH NMR: consistent with the structure.
WO 95/02587 WO 9502587PCT/US94/07769 53 EXAMPLE 21 I -(2-Methiylphenyl)-4-[(4,7 ,7-trimethyl-3 -endo-(4-methylsulfonyl-2-(4tetrahydropyranyl)amino) butanoylamino bicyclo [2.2.1 ]hept-2-endol)carbonvl-p2iperazine 100 010- H HN Q N
CH
3 0 To a solution of 1 -(2-methylphenyl)-4-[(4 ,7 ,7-trirnethyl-3end o-(4 -methylIsulIfonyl -2-amino)-butano ylIamino bicyclo [2.2.1 ]hept-2endo-yl)carbonyl]-piperazine (150 mg, 0.28 mmol) in 1% acetic acid/methanol (5 mL) at 0 0 C was added pyran-4-one (0.072 mL, 0.34 mmol) followed by sodium cyanoborohydride (21 mg, 0.34 inmol).
After 18 h, the mixture was concentrated, then partitioned between ethyl acetate and brine (50 mL each). The ethyl acetate solution was dried over magnesium sulfate, then concentrated. The title compound was purified by flash chromatography (2:1 hexanes:ethyl acetate as eluant) to afford 1 10 mg of white solid.
TLC: Rf (95:5:0.5 chloroform:methanol: ammoni urn hydroxide)= 0.18 Analysis: (C32H50N405S 1) 0. 1 chloroform calc. C, 62.71; H, 8.21; N, 9.11 found C, 62.47; H, 8.24; N, 9.14 HPLC: (method A) Rt 10.34 min.
WO 95/02587 PTU9/76 PCTIUS94/07769 54 FABMS: m/z 603 H) 'H NMR: consistent with the structure.
EXAMPLE 22 General Procedure for the Diels-Alder Reaction: To a solution of dienophile in toluene was added the diene.
The temperature was increased to reflux. After 2 days the mixture was to yield crude cycloadduct.
EXAMPLE 23 1 -(2-methylphenyl)-4-[spiro(bicyclo[2.2. 1 ]hept-5-ene-7, 1 -cyclopropan -2-en do -ethoxycarbonyl -3 -ex 9-vl carbonyl I -piperazine and 1 -(2-methylphenyl)-4-[spiro(bicyclo[2.2. 1 ]hept-5-ene-7,l F-cyclopro- -an -2-ex o-etlioxycarbonyl 3-end o-vl)carbonvl I-piperazine EtO 2
C,
N-
OH
3 0 Spiro[ 2.4] hepta-4,6-diene and ethyl, o-tolylpiperazinyl fumnarate were condensed as described in the General Procedure for the Diels-Alder Reaction. The title compounds were separated and purified by flash chromatography (10% ethyl acetate in petroleum ether as eluant).
WO 95/02587 WO 9502587PCTIUS94/07769 55 Analysis: (C24H3ON203) 0.12 water caic. C, 72.64; H, 7.70; N, 7.06 found C, 72.55; H, 7.83; N, 6.73 HPLC: (method A) Rt 12.91 min.
FABMS: m/z =395
+H)
IH NMIR: consistent with structure.
Analysis: (C24H30N203) caic. C, 73.05; H, 7.68; N, 7.10 found C, 72.74; H, 7.84; N, 6.81 HPLC: (method A) Rt 12.22 min.
FABMS: m/z 395 H) 1H NMR: consistent with structure.
EXAMPLE 24 1 -(2-methiylphenyl)-4- [spiro(bicycloj2.2.l1 hept-5 -ene-7, 1'-cyclopropan -2-en do-carboxvAl-3 -ex o-vlI)carbony I I-12i erazine H0 2
C
;H
OH
3 0 To a solution of I -(2-methylphenyl)-4-Ijspiro(bicyclo- 1 ]hept-5-ene-7, 1 '-cyclopropan-2-endo-ethoxycarbonyl-3-exoyl)carbonylll-piperazine (700 mg, 1.8 mmol) in tetrahydrofuran (13.8 mL) was added a 1 M aqueous solution of lithium hydroxide (18 mL, 18 mmnol). After stirring for 18 h at room temperature followed by 18 h at 50'C, the mixture was concentrated then partitioned between ethyl acetate and 1 M HCl (75 mL each). The ethyl acetate layer was dried WO 95/02587 WO 9502587PCTIUS94/07769 56 over sodium sulfate then concentrated to yield 580 mg of the title compound.
185-187C Analysis: (C22H26N203) 0.5 water caic. C, 70.36; H, 7.26; N, 7.46 found C, 70.75; H, 6.91; N, 7.67 HEPLC: (method A) Rt 10.62 min.
FABMS: m/z 367 H) 1 H NMR: consistent with the structure.
EXAMPLE 1 -(2-methylphenyl)-4-[spiro(bicyclo[2.2. 1 ]hept-5-erie-7, 1 -cycloprop2an-2-(t-butox vcarbonyl) amino -3 -yI Dcarbonyl11 -piperazine
HN
N N/
OH
3 0 To a solution of 1-(2-methylphenyl)-4-Ilspiro(bicyclo- 1 ]hept-5-ene-7, 1 '-cyclopropan-2-carboxyl-3-yI)carbonyl] piperazine (200 mg, 0.54 mmol) in t-butanol (4 mL) was added diphenylphosphorylazide (DPPA, 0.12 mL, 0.57 inmol) followed by the dropwise addition of triethylamine (0.08 mL, 0.58 mmol). The temperature was increased to reflux. After 1 h, CuCI (11I mg, 0.111 mmol) was added. After 2 h, the mixture was cooled, diluted with diethyl ether (50 mL) then washed with I M sodium hydroxide, water, and brine. The ethyl ether layer was dried over sodium sulfate, then WO 95/02587 WO 9502587PCTIUS94/07769 57 concentrated to an orange foam. The title compound was purified by flash chromatography ethyl acetate in hexanes as eluant) to yield 82 mg of pure product.
164-166'C Analysis: (C26H35N303) 0.75 water caic. C, 69.21; H, 8.17; N, 9.32 found C, 69.53; H, 8.56; N, 9.46 HPLC: (method A) Rt 13.17 min.
FABMS: m/z =438 +H) IH NMR: consistent with the structure.
EXAMPLE 26 1 -(2-methylphenyl)-4-[spiro(bicyclo[2.2. 1 ]hept-5-ene-7, I -cyclopropan-2-(2-ethvlmercaptoethyl) aminocarbonvi -3-v 'carbonyll -piperazine 200 N
N
C H 3 0 To a solution of 1 -(2-methylphenyl )-4-[spiro(bicyclo- [2.2.1 ]hept-5-ene-7, 1 '-cyclopropan-2-endo-carboxyl-3-exo-yl)carbonyl]-piperazine (75 mg, 0.20 mmol) in dimethylformamide (3 rnL) was added 2-(ethylthio)ethylamine hydrochloride (28 mg, 0.2 mmol), N-ethyl, N',N'-(dimethylamino)propyl carbodiimide (EDC, 38 mg, 0.2 mmol), hydroxybenzotriazole (27 mg, 0.2 mmol), and triethylamine (0.055 mL, 0.4 m-mol). After stirring at room temperature for 18 h, the mixture was diluted with ethyl acetate mL) d e~n washed with saturated aqueous sodium bicarbonate and brine mnL each), then dried over sodium sulfate and concentrated. The WO 95/02587 WO 95/2587 CT/US94/07769 58 title compound was isolated with flash chromatography (40% ethyl acetate in hexanes as eluant) to yield 64 mg.
111-112'C Analysis: (C26H35N302S) 0.5 water caic. C, 67.48; H, 7.86; N, 9.08 found C, 67.35; H, 7.87; N, 8.93 HIPLC: (method A) Rt 10.27 min.
FABMS: mlz 454 H) IH NMR: consistent with the structure.
EXAMPLE 27 1 -(2-methylphenyl)-4-[spiro(bicyclo [2.2.1 ]heptane-7,1I'-Cyclopropan-2ethoxv arbonvl -3-vl)curbonvili-p2iperazine EtO 2
C
N N
OH
3 0 To a solution of 1-(2-methylphenyl)-4-[spiro(bicyclo- [2.2.1 ]hept-5-ene-7, 1 '-cyclopropan-2-enido-carboxyl-3-exo-yI)carbonyll-piperazine (1 g, 2.5 mmol) in ethanol (28 ml) was added palladium on carbon (100 mg). The mixture was then placed uinder hydrogen atmosphere at room pressure. After 3 h, the mixture was filtered then concentrated to yield 1 g.
102-103'C Analysis: (C24H3IN203) calc. C, 72.68; H, 8.15; N, 7.06 found C, 72.43; H, 8.08; N, 7.08 WO 95/02587 PCT/US94/07769 -59- HPLC: (method A) Rt 14.15 min.
FABMS: m/z 397 H) 1 H NMR: consistent with the structure.
EXAMPLE 28 1-(2-methylphenyl)-4-[spiro(bicyclo[2.2. I1]heptane-7,1 '-cyclopropan- 2-(N.N-diethyl amino)carbonvl-3 -yl)carbonvll -piperazine
N
N N
CH
3
O
Part I: To a solution of 1-(2-methylphenyl)-4-[spiro-(bicyclo- [2.2.1 ]hept-5-ene-7,1 '-cyclopropan-2-ethoxycarbonyl-3-yl)carbonyl]piperazine (390 mg, 1.06 mmoL in ethanol (12 mL) was added palladium on carbon (39 mg). The mixture was then placed under hydrogen atmosphere at room pressure. After 18 h, the mixture was filtered and concentrated to yield 390 mg of the carboxylic acid.
Part 1: To a solution of the carboxylic acid from part I (75 mg, 0.20 mmol) in dimethylformamide (3 mL) was added diethylamine (0.062 mL, 0.44 mmol), N-ethyl, N',N'-(dimethylamino)propyl carbodiimide (EDC, 38 mg, 0.2 mmol), and hydroxybenzotriazole (27 mg, 0.2 mmol). After stirring at room temperature for 18 h, the mixture was diluted with ethyl acetate (50 nmL) then washed with saturated aqueous sodium bicarbonate and brine (50 mL each), then dried over sodium sulfate and concentrated. The title compound was WO 95/02587 WO 9502587PCT/US94/07769 60 isolated with flash chromatography (30% ethyl acetate in hexanes as eluant) to yield 91 mg as an amorphous foam.
Analysis: (C26H37N302) 0.5 water caic. C, 72.17; H, 8.87; N, 9.71 found C, 72.16; H, 8.66; N, 9.50 HPLC: (method A) Rt 13.05 min.
FABMS: m/z 424 H) IH NMR: consistent with the structure.
EXAMPLE 29 I -(2-methylphenyl)-4-[spiro (bicyclori2.2.1 ]heptane-7 ,1I'-cyclopropan-2- (2-(NN-dimeth laminoethvl~amino) carbonvl-3-vl)carbonvll-piperazine H3CN, /0CH 3
H
N
N N
CH
3 0 To a solution of l-(2-methylphenyl)-4-Ilspiro(bicyclo- [2.2.1 ]heptane-7,1I'-cyclopropan-2-carboxyl-3-yl)carbonyl]-piperazine mg, 0.20 mmol) in dimethylformamide (3 m.1) was added N,N- (dimethylaminoethyl)amine (0.097 mL, 0.80 mmol), N-ethyl, (dimethylamnio)propyl carbodiimide (EDC, 50 mg, 0.26 mmol), and hydroxybenzotriazole (35 mg, 0.26 rnol). After stirring at room temperature for 1 8 h, the mixture was diluted with ethyl acetate mL) then washed with saturated aqueous sodium bicarbonate and brine mL each), then dried over sodium sulfate and concentrated. The title compound was purified by flash chromatography (92:8:0.8 chloroform:methanol:amnmonium hydroxide as eluant).
WO 95/02587 WO 9502587PCT/US94/07769 61 158-159'C Analysis: (C26H38N402) 0.5 water caic. C, 69.75; H, 8.80; N, 12.52 found C, 70,01; H, 8.45; N, 12.34.
HPLC: (method A) Rt =I 10. 10 min.
FABMS: m/z 439 H) H NMR: consistent with the structure.
EXAMPLE I -(2-methylphenyl)-4-[spiro(bicyclol2.2. I ]heptane-7, I -cyclopropan-2- (2-hydroxyethvl~amino) carbonyl -3 -y )carbon yl -p2iperazine OHH0
N
~N N OHi 3 0 To a solution of 1-(2-methiylphenyl)-4-[spiro(bicyclo- 1 ]heptane-7, 1 '-cyclopropan-2-carboxyl-3-yl)carbonylj-piperazine mg, 0.24 mmol) in methylene chloride (5 mL) was added dimethylformamide (1 drop), followed by oxallyl chloride (0.032 mL, 0.36 mmol). After 2 h, the mixture was concentrated, redissolved in methylene chloride (3 mL), then ethanolamine (0.5 mL) was added.
After 18 h, thle mixture was diluted with methylene chloride (50 mL), then washed with saturated aqueous sodium bicarbonate and brine mL each), then dried over sodium sulfate and concentrated. The title compound was purified by flash chromatography (100% ethyl acetate as eluant).
173-174'C Analysis: (C24H33N303) WO 95/02587 PCT/US94/07769 -62calc. C, 70.03; H, 8.10; N, 10.21 found C, 69.67; H, 8.01; N, 9.99 HPLC: (method A) Rt 10.22 min.
FABMS: m/z 412 H) 1H NMR: consistent with the structure.
EXAMPLE 31 1 -(2-methylphenyl)-4-[spiro(bicyclo[2.2. I]heptane-7,1 '-cyclopropan- 2-hydroxvmethvl-3-vl)carbonvll-piperazine
HO
N N
CH
3 O To a solution of 1-(2-methylphenyl)-4-[spiro(bicyclo- [2.2.1]heptane-7,1'-cyclopropan-2-carboxyl-3-yl)carbonyl]-piperazine mg, 0.14 mmol) in tetrahydrofuran (2 mL) at 0°C was added dropwise a solution of borane in tetrahydrofuran (1 M, 0.03 mL, 0.30 mmol). After 1 h, 1 M HCI was added (5 drops), and stirring was continued at room temperature. After 1 h, aqueous sodium carbonate was added until pH> 7, then the mixture was washed with ethyl acetate (2 X 50 mL). The ethyl acetate extracts were washed with brine, then dried over sodium sulfate and concentrated. The title compound was purified by flash chromatography (a graedient from 40% to 50% ethyl acetate in hexanes as eluant) to afford 30 mg of white solid.
141-143°C Analysis: (C22H30N202) 0.5 water calc. C, 72.68: H, 8.61; N, 7.71 found C, 72.97; H, 8.44; N, 7.67
Y_
WO 95/02587 PCT/US94/07769 -63 HPLC: (method A) Rt 11.39 min.
FABMS: m/z 355 H) 1H NMR: consistent with the structure.
EXAMPLE 32 1-(2-methylphenyl)-4-[spiro(bicyclo[2.2. 1 ]heptane-7,1 '-cyclopropan- 2-pivalvloxmethl -3-yl)carbonvll -piperazine 0 0 N N
CH
3 O To a solution of 1-(2-methylphenyl)-4-[spiro(bicyclo- [2.2.1 ]heptane-7, 1 '-cyclopropan-2-hydroxymethyl-3-yl)carbonyl]piperazine (65 mg, 0.18 mmol) in pyridine (2 mL) was added N,Ndimethylaminopyridine (17 mg, 0.14 mmol) followed by trimethylacetyl chloricd (0.031 mL, 0.27 mmol). After 18 h, the mixture was diluted with ethyl acetate (50 mL), washed with 10% aqueous citric acid and brine (50 mL each), then dried over sodium sulfate and concentrated. The title compound was purified by flash chromatography (10% ethyl acetate in hexanes as eluant) to yield an amorphous foam.
Analysis: (C27H38N203) 0.7 water calc. C, 71.86; H, 8.80; N, 6.21 found C, 71.92; H, 8.56; N, 6.11 FABMS: m/z 439 H) IH NMR: consistent with the structure.
WO 95102587 WO 9502587PCT[US94/07769 64 EXAMPLE 33 I -(2-methylphenyl)-4-Ijspiro(bicyclo[2.2. I Ihept-5-ene-7, 1 '-cycloprop2an-2-butoxycarbonvl-3-vI )carbony-f-ihlierazine 0 0-
N
OH
3 0 To a solution of 1 -(2-methyl.phenyl)-4-[spiro(bicyclo- [2.2.1 ]hept-5-ene-7 ,1 '-cyclopropan-2-carboxyl -3-yl)carbonyl] piperazine (86 mg, 0.23 mmr' methyl ene chl oride (3 mL) was added dimethylformamide (1 drop) t-Illowed by oxallyl chloride (0.03 mL, 0.35 mmol). After 2 h, the mixi-are was concentrated, then redissolved in methylene chloride (0.5 mL) and added to a solution of butanol (3 mL) and triethylamine (0.32 mL, 2.3 mmnol). After 18 h, the mixture was diluted with ethyl acetate (70 mL), washed with water and brine mL each), dried over sodium sulfate and concentrated. Purification by flash chromatography (10% ethyl acetate in hexanes as eluant) to yielded 45 mg of the title compound as an oil.
Analysis: (C26H3'4N203) 0.35 ethyl acetate caic. C, 72.59; H, 8.18; N, 6.18 found C, 72.53; H, 8. 10; N, 6.34 FABMS: m/z 423 H) IH NMR: consistent with the structure.
WO 95/02587 PCT/US94/07769 65 EXAMPl.L 34 1 -(2-methylphenyl)-4-[spiro(bicyclo[2.2.1 ]hept-5-ene-7,1 '-cyclopropan-2-(2-pyridinemethvloxy)carbonvl-3-vylcarbonyl]-piperazine
O
CHa O To a solution of 1-(2-methylphenyl)-4-[spiro(bicyclo- [2.2.1]hept-5-ene-7,1'-cyclopropan-2-carboxyl-3-yl)carbonyl]piperazine (75 mg, 0.20 mmol) in methylene chloride (3 mL) was added dimethylformamide (1 drop) followed by oxallyl chloride (0.18 mL, 2 mmol). After 2 h, the mixture was concentrated, then redissolved in methylene chloride (2 mL). Triethylamine (0.28 mL, 2 mmol) was added, followed by 2-pyridyl carbinol (3 mL). After 18 h at room temperature, the mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate (75 mL each). The ethyl acetate layer was washed with water (2 X 70 mL), brine (50 mL), then dried over sodium sulfate and concentrated. Purification by flash chromatography (10% ethyl acetate in hexanes as eluant) afforded 58 mg of the title compound as an amorphous foam.
Analysis: (C28H31N303) 0.80 ethyl acetate calc. C, 70.97; H, 7.14; N, 7.96 found C, 70.95; H, 6.92; N, 8.12 HPLC: (method A) Rt 9.98 min.
FABMS: m/z 458 H) 1H NMR: consistent with the structure.
WO 95/02587 PCT/US94/07769 -66- EXAMPLE 1 -(2-methylphenyl)-4-[spiro(bicyclo[2.2.1 ]hept-5-ene-7,1 '-cyclopropan-2-(2-piperidinemethyloxy)carbonvl-3-yl)carbonyl]-piperazine N 0
H
N N
CH
3
O
Part I: To a solution of 1-(2-methylphenyl)-4-[spiro(bicyclo- ]hept-5-ene-7,1'-cyclopropan-2-carboxyl-3.-yl)carbonyl]piperazine (93 mg, 0.25 mmol) in methylene chloride (3 mL) was added dimethylformamide (1 drop) followed by oxallyl chloride (0.22 mL, 2.5 mmol). After 2 h, the mixture was concentrated, then redissolved in methylene chloride (0.5 mL). Triethylamine (0.34 mL, 2.5 mmol) was added, followed by N-boc 2-piperidinylmethanol (540 mg, mmol). After 18 h at room temperature, the mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate (90 mL each). The ethyl acetate layer was washed with water (2 X 90 mL), brine (75 mL), then dried over sodium sulfate and concentrated. Purification by flash chromatography (a gradient from to 20% ethyl acetate in hexanes as eluant) afforded 113 mg of the intermediate N-boc ester.
Part II: To a solution of the N-boc derivative prepared in part I (100 mg, 0.18 mmol) in methylene chloride (5 mL) at 0°C was added trifluoroacetic acid (5 mL). After stirring at 0°C for 30 min, the mixture was paritioned between methylene chloride and saturated ~Cr~R_ I ~a WO 95/02587 PCT/US94/07769 67 aqueous sodium bicarbonate (100 mL each). The methylene chloride was washed with water and brine, then dried over sodium sulfate and concentrated. Purification by flash chromatography isopropanol in chloroform as eluant) afforded 54 mg of the title compound as a solid.
144-146°C Analysis: (C28H37N303) 1.0 water calc. C, 69.81; H, 8.18; N, 8.73 found C, 69.84; H, 7.90; N, 8.61 HPLC: (method A) Rt 10.30 min.
FABMS: m/z 464 H) 1 H NMR: consistent with the structure.
EXAMPLE 36 1-(2-methylphenyl)-4-[(4,7,7-trimethyl-3-oxobicyclo[2.2.1 ]hept-2yl)sulfonyll-piperazine r CH 3 N 0
N
0 0 To a solution of o-tolylpiperazine (560 mg, 3.18 mmol) in methylene chloride (10 mL) at 0°C was added camphor-a-sulfonyl chloride (prepared by the route of M. Frerejacque Comp. Rend. 1926, 187, p. 895, 810 mg, 3.18 mmol). Triethylamine was added until the pH was approximately 9. After 1 h, the mixture was diluted with methylene chloride (50 mL), then washed with water (2 X 50 mL) and brine, then dried over sodium sulfate and concentrated. Purification by flash chromatography (3:1 hexanes: ethyl acetate as eluant) afforded 860 mg of the title compound as a white amorphous foam.
a3 CIb" I-- WO 95/02587 PCT/US94/07769 -68 TLC: Rf (3:1 hexanes:ethyl acetate) 0.56 Analysis: (C21H30N203S) calc. C, 64.58; N, 7.74; H, 7.17 found C, 64.88; N, 7.91; H, 7 01 FABMS: m/z 391 H) 1H NMR: consistent with structure.
EXAMPLE 37 1 -((7,7-Dimethyl-2-oxo-bicyclo(2.2.1 )heptan- -yl)methanesulfonyl)-4- (2-methylphenyl)-piperazine
CH
3
N
N
S02 0 To a stirred, 0°C solution of 1-(o-tolyl) piperazine hydrochloride (50.0 g; 235 mmol) and TEA (83 mL; 590 mmol) in chloroform (1000 mL) was added (+)-10-camphorsulfonyl chloride (65.5 g; 260 mmol). The solution was stirred at 0°C for 1 h and then at ambient temperature for 3 h. The solution was extracted with aqueous HCI (2 x 500 mL), water (500 mL), and saturated aqueous NaHCO3 (2 x 500 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The resulting solid was recrystallized from methanol to give the title compound, mp 112-114°C (69 g; WO 95/02587 PCT/US94/07769 69 Analysis (C2 1H30N203S) caic. C, 64.57; H, 7.74; N, 7.17 found C, 64.52; H, 7.68; N, 6.99 TLC: Rf 0.49 (75:25 hexane/ethyl acetate) HPLC (method retention time 10.33 min FAB MS: m/z 391 +H) I H NMR (300 MI-z, CDCI3): 8 7.2 (in, 2H), 7.0 (in, 2H), 3.45 (in, 4H), 3.40 J= 16 Hz, I1-H), 3.0 (in, 4H), 2.57 (in, I 2.40 (dt, Jd= 14 Hz, Jt=3 Hz, 1H), 2.30 3H), 2.10 (in, 2H), 1.96 J=14 Hz, IH), 1.67 (in, 1H), 1.44 (in, 1H), 1.18 3H), 0.91 3H).
EXAMPLE 38 1 ,7-Diinethyl-2-exo-hydroxy-2-endo-( 1 -cyano)ethyl-bicyclo(2.2. 1)hep~tan- I -vl)methanesulfonvl )-4-(2-methvlphenvl)-piperazine C H 3 a
N,
S0 2
OH
H
3 0 ON To a stirred, -78'C solution of diisopropylainine (21.0 rnL; 150 mmrol) in THF (350 inL) was added n-butyllithiuin (60 mL of a M solution in hexane; 150 inmol). The solution was warmed to 0 0 C for min, then cooled to -78'C. A solution of propionitrile (10. 1 mL; 141 inmol) in THF (75 rnL) was added dropwise, and the resulting solution was stirred at -78'C for 45 min. A -78'C solution of dimethyl-2-oxo-bicyclo(2.2. 1 )heptan- 1 -yl)rnethane-sulfonyl)-4-(2- WO 95/02587 PCT/US94/07769 70 methylphenyl)piperazine (50.0 g; 128 mmol) in THF (350 mL) was added via cannula, and the resulting solution was stirred at -78 0 C for min. A solution of 5:1 THF/water (100 mL) was added and the mixture was warmed to ambient temperature. The mixture was diluted with EtOAc (500 mL) and washed with 5% aqueous citric acid (2 x 500 mL), and brine (250 mL). The organic phase was dried (MgSO4), filtered, and the solvents were removed under reduced pressure to give a foam.
The major isomer by TLC was obtained by crystallization from ether, mp 163-165 0
C.
Analysis: (C24H35N303S) calc. C, 64.69; H, 7.92; N, 9.43 found C, 64.72; H, 7.99; N, 9.35 TLC: Rf0.31 (75:25 hexane/ethyl acetate) HPLC (method retention time 10.20 min FAB MS: m/z 446 H) 1H NMR (300 MHz, CDC13): 5 7.19 2H), 3.70 J=15 Hz, 1H), 3.68 1H), 3.49 4 3.38 J=15 Hz, H), 2.75 J=7 Hz, 1H), 2.30 2H), 2.05 2H), 1.7-1.9 3H), 1.47 J=7 Hz, 3H), 1.41 J=12 Hz, 1H), 1.40 3H), 1.15 3H), 1.04 1H).
EXAMPLE 39 1-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1 -amino)-propylbicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-2-methylphenyl)piperazine WO 95/02587 PCT/US94/07769 -71
.CH
3
N
O, OH
H
3 C
OH
NH
2 To a stirred, -78 0 C solution of dimethyl-2-exohydroxy-2-endo-(l -cyano)ethyl-(2.2.1) bicycloheptan-1 -yl)methanEsulfonyl)-4-(2-methylphenyl)piperazine (25.0 g; 56.2 mmol) in THF (350 mL) was added dropwise a 1.0 M solution of LAH in THF (170 mL; 170 mmol). The resulting solution was stirred at -78 0 C for 1 h, and then warmed to 0 C for 3 h. Ether (300 mL) was added, followed by the slow drop-wise addition of 5 M NaOH solution (35 mL). The resulting suspension was warmed to ambient temperature and stirred for 1 h. EtOAc (250 mL) was added and stirring was continued for min. The solids were removed by filtration through Celite and washed with EtOAc. The filtrate sovents were removed under reduced pressure to give a foam. The title compound was obtained by crystallization from methanol (17.2 g; mp 172-174°C.
Anal: (C24H39N303S) calc. C, 64.11; H, 8.74; N, 9.35 found C, 64.09; H, 8.88; N, 9.31 TLC: Rf0.50 (95:5:0.5 CHCI3/MeOH/NH40H) HPLC (method retention time 9.80 min FAB MS: m/z 450 H) 1 H NMR (300 MHz, CDC13): 5 7.20 2H), 7.05 2H), 2.32 (s, 3H), 1.13 J=6 Hz, 3H), 1.11 3H), 1.02 3H).
-r I WO 95/02587 WO 9502587PCIVUS94/07769 72 EXAMPLE 1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-( I -(l-prolyl).-amino)propylbicyclo(2.2. I )heptan- 1 -yl)miethanesulfonyl)-4-(2-methylphenyl)piperazine IM H 3 10S0
OHO
CH
N' C
N
H H To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2- 20endo-2-( 1-amino) propyl-(2.2. 1 )bicycloheptan- I -yl)methanesulfonyl)- 204-(2-methylphenyl)piperazine (2.00 g; 4.45 mmol) in DMF (30 mL) was added Na-Fmoc-L-proline (1.58 g; 4.68 mmol), BOP (2.17 g; 4.90 mmol), and DIEA (1.71 mL; 9.80 mmol). After 16 h, diethylamine (6 mL) was added and the solution was stirred at ambient temperature for 3 h. The solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acatonitrile-water gradient containing 0. 1 TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C29H46N404S) calc. C, 52.48; H, 6.50; N, 7.56 found C, 52.46; H, 6.50; N, 7.69 1.7 TFA, 0.05 TLC: Rf 0.45 (90: 10:1 CHCI3:MeO-1:N-140H) 1-PLC (method retention time 8.60 min WO 95/02587 CTU4/76 PCT/US94/07769 73 FAB MS: rn/z 547 H) I H NMR (400 MHz, CDCI3): 567.55 (br t, I 7. 18 (in, 2H), 7.03 (mn, 2H), 2.31 3H), 1. 14 3H), 1.02 3H), 0.99 J=7 Hz, 3H).
EXAMPLE 41 1 ,7-Dimnethyl-2-exo-hydroxy-2-endo-2-( 1 -N-(ethoxycarbonylpropylI)pro lyl)amino)p ropylI-bicyc lo(2.2. I )heptan- I -yl)methanesulfonyl)-4-(2-methylp~henvl)-piperazine .0H 3 To a stirred solution of 1 ,7-dimethyl-2-exo-hydroxy-2- 25endo-2-( 1 -(L-prolyl)atr,. Ipropyl-(2.2. 1)bicycloheptan- 1-yl)methane- 25sulfonyl)-4-(2-methylphenyl)-piperazine (1.50 g; FW=679; 2.21 rimol) in DMF (15 m.L) was added ethyl 4-bromobutyrate (538 mng; 2.76 mmol), and DEEA (1.15 mL; 6.63 mrnol). After 72 h at ambient temperature, the solvent was removed under reduced pressure and the was purified by preparative reverse phase I-PLC using an gradient containing 0. 1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
WO 95/02587 WO 9502587PCT/US94/07769 74 Analysis: (C35H56N406S) cabc. C, 51.99; H, 6.48; N, 6.17 found C, 52.01; H, 6.33; N, 6.17 2.1 TFA, 0. 1 TLC: Rf 0.40 (95:5 CHC13:MeOH) HPLC (method retention time 10.23 min FAB MS: m/z 661 +H) I H NMR (400 MHz, CDCI3): 8 8.55 (in, 1H), 7.20 (in, 2H), 7.08 (in, 2H), 2.35 3H), 1.25 J=6Hz, 3H), 1.14 3H), 1.03 (overlapping s and d, 6H).
EXAMPLE 42 1 ,7-Dimethyl-2-exo-hydroxy-2-endo-2-(1 -(1-N-(3-carboxypropyl)prolyl)amino)propyl-bicyclo(2.2. I )heptan- 1 -yl)methanesulfonyl)-4-(2mehy heny1)-pip erazine
CH
3 S0 2 OHO 0 0 2
H
NN
H
To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2endo-2-( 1-(L-N-(ethoxycarbonylpropyl) prolyl)amino)propyl- )bicycloheptan- 1-yl)methanie- sulforiyl)-4-(2-methylplienyl)piperazine (1.00 g; PW=909; 1.10 minol) in THF (15 mE) was added 1 M NaOH1 solution (1.0 mL; 4.0 minol) until a pH 10 solution persisted WO 95/02587 PCT/US94/07769 for 1 h. The solution was acidified to pH 7 by addition of citric acid and the solvents were removed under reduced pressure. The residue was dissolved in dichloromethane (75 mL) and washed with water (3 x mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was lyophilized from dioxane-water to give the title compound as a white powder.
Analysis: (C33H52N406S) calc. C, 59.78; H, 8.25; N, 6.94 o0 found C, 59.86; H, 7.98; N, 6.92 0.1 Na citrate, 1.65 dioxane TLC: Rf 0.35 (80:20:2 CHCL3:MeOH:NH40H) HPLC (method retention time 9.24 min FAB MS: m/z 633 H) 1 H NMR (400 MHz, CDC13): 5 7.55 (br s, 1H), 7.18 2H), 7.03 (m, 2H), 2.31 3H), 1.15 3H), 1.04 3H), 0.98 J=6 Hz, 3H).
EXAMPLE 43 1-((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(1-(4(5)-imidazolylacetyl)amino)propyl-bicyclo(2.2.1 )heptan-1 -yl)methanesulfonyl)-4-(2methylphenyl)-piperazine
CH
3
N
Ns
H
N
OHO 0 WO 95/02587 WO 95/2587 CT[US94/07769 76 To a stirred solution of l-((7,7-dimethyl-2-exo-hydroxy-2endo-2-( 1 -amino)propyl-(2.2. 1 )bicyclo-heptan- I -yI)methane-sulfonyl) 4-(2-methylphenyl)piperazine (1.50 g; 3.34 mmnol) in DMF (15 mL) was added 4(5)-imidazole acetic acid hydrochloride (679 mg; 4.18 mrmoD',, BOP (1.85 g; 4.18 mmol), and DIBA (2.18 mL; 12.5 mmol).
After 16 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mEL) and washed with saturated aqueous NaHCO3 solution (2 x 50 mL) and water (2 x 50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8:0.8 (CHCJ 3:MeOH:NI-40H) as eluant. Ths title compound crystallized from EtOAc, mp 159-163'C.
Analysis: (C29H43N504S) calc. C, 62.45; H, 7.77; N, 12.56 found C, 62.88; H, 7.68; N, 12.79 TLC: Rf 0.4 (90:10:1 CHCI3/MeOH/NI-40H) HPLC (method .:retention time 8.72 min FAB MS: m/z 558 +H) 1 H NMR (CDCI3): 8 7.57 1H), 7.2 (in, (in, 2H). 6.88 I1H), 3.55 (in, 2H), 3.4 (in, 5H), 2.95 (in, 4H), 2.87 (d, J= 15 Hz, I1H), 2.31 3H), 1.71 J=4 Hz, I1H), 1.52 J= 13 Hz, I H), 1.15 3H), 1.03 3H), 0.97 J=6 Hz, 3H).
EXAMPLE 44 1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1 -(quinuclidin-3-ylcarbonyl)amino)propyl-bicyclo(2.2. 1 )heptan-lI -yl)methanesulfonyl)-4- (2-methVlphenvl)-pDiperazine WO 95/02587 WO 95/2587 cr/uS94107769 77
OH
3
N
SO
2 i' OHO 11 To a stirred solution of 1 cimethyl-2-exo-hydroxy- 2-endo-2-(l1-amino)propyl-(2.2. 1)bicycloheptan- 1-yl)methanesulfonyl)- 4-(2-methylphenyl)piperazine (2.00 g; 4.45 mmol) in DMF (50 mL) was added quinuclidine-3-carboxylic acid hydrochloride (938 mg; 4.90 mmol BOP (2.17 g; 4.90 mmol), and DIEA (2.56 m.L; 14.7 mmol).
After 16 h, the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1% acetic acid. The acetate salt of the title compound 1 mixture of diastereomers) was obtained as a lyophilized powder.
Analysis: (C32H50N404S) calc. C, 60.39; H, 8.58; N, 8.39 1Vfound 60.41; H, 8.19; N, 8.58 0.8 CH3CO2H, 1.85 TLC: Rf 0.65 (80:20:2 CHCI3:MeOH:NH-40H) HPLC (method retention time 8.68 mini FAB MS: m/z 587 +H) I H NMR (300 MHz, CDCI3): 8 7.19 (in, 2H), 7.02 (in, 2H), 2.30 (s, 3H), .16 3H), 1.03 (over-lapping s and d, 6H).
WO 95/02587 WO 9502587PCTIJS94/07769 78 EXAMPLE 1 -((7,7-Dimethyl-2-exo-hydroxy-2-tndo-2-( 1 -carboxymethylquinuclidin-3-yl-carbonyl)amino)propyl-bicyclo-(2.2.1 )heptan- 1 ylmethanesulfonfl)-4-(2-methylphenvl)-piperazine
OH
3 C N S0 2
OHO
N'C--6<00 2
H
H K To a stirred solution of 1-((7,7-dimethyl-2-exo-hydrcxy-2endo-2-( 1 -(quinuclidini-3-yl-carbonyl)amino)-propyl-(2.2. 1 )bicycloheptan- I -yl)methane-sulfonyl)-4-(2-methylphenyl)piperazine (1.50 g; FW=668, 2.25 mmol) in DMF (30 mL) was added iodo-acetic acid (543 mg; 2.92 mmol) and DJEA (0.43 mL; 2.48 mmnol). After 16 h, TLC showed complete consumption of starting material. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an a-.etonitrile-water gradient containing 1 OX acetic acid. The title compound, as a 1: 1 mixture of diastereomners, was obtained as a lyophilized powder.
(C34H52N404S) calc. C, 60.52; H, 8.18; N, 8.04 found C, 60.52; H, 7.98; N, 8.15 0.55 CH3CO2H, 0.95 TLC: Rf 0.20 (80:10:2 CHCl3:MeOH:NH4OH) WO 95/02587 WO 9502587PCI'/US94/07769 79 HPLC (method retention time 8.73 min FAB MS: m/z 647 H) I H NMR (TFA salt; 400 MHz, CDCl3): 5 7.46 (br s, 1H), 7.19 (in, 2H), 7.02 in, 2H), 2.30 3H), 1.13 3H), 1.02 3H), 0.98 J=6 Hz, 3H).
EXAMPLE 46 1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1-(2-methoxycarbonylethyl)-amino)propyl-bicyclo(2.2. 1 )heptan- 1 -y1) -methane sulfonyl1)-4-(2m-.th ip hen yl-pip erazine
CH
3 1
N
N
S0 %I OH N C2CH3
H
To a stirred solution of l-((7,7-dimethyl-2-exo-hydroxy-2- 25endo-2-( 1 -amino)propyl-(2 1) bicycloheptan- I -yl)methanesulfonyl)-4- (2-methylphenyl)piperazine (100 nig; 0.22 mmnol) in 1: 1 DMF-MeOH (3 mL) was added methyl acrylate (0.020 rnL; 0.22 mmol). After 16 hi, the solvents were removed under reduced pressure and the residue was by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% TFA. The TFA salt of the title compound was obtained as a lyophilized powder.
WO 95/02587 WO 9502587PCT[US94/07769 80 Analysis: (C28H45N305S) caic. C, 53.03; H, 6.88; N, 6.06 found C, 53.01; H, 6.90; N, 6.01 1.3 TFA, 0.5 TLC: Rf 0.35 (95:5 (CHCl3:MeOH) HPLC (method retention time 9.04 min FAB MS: m/z536 +H) I H NMR (300 MHz,, CDCl3): 5 7.20 (in, 2H), 7.03 (mn, 2H), 3.72 (s, 3H), 2.32 3H), 1.19 J=6 Hiz, 3H), 1.15 3H), 0.98 3H).
EXAMPLE 47 1 -((7,7-dimnethyl-2-exo-hydroxy-2-endo-2-( 1 -bis-(2-methoxycarbonyl- 15ethyl)amino)propyl-bicyclo(2.2. 1 )heptan- 1 -yl)inethanesulfonyl)-4-(2methylp~henyl)-pip~erazine
OH
3
N..
SO
2 III,
OH
,\C
2
CH
3 To a stirred solution of 1-((7,7-diinethyl-2-exo-hydroxy-2endo-2-( -amnino) -prop yl 1 )bicycloheptan- 1 -yl)methanesulfonyl)-4- (2-methylphenyl)piperazine (100 mg; 0.22 inmol) in 1: 1 DMF-MeOH (3 mL) was added methyl acrylate (0.080 inL); 0.89 inmol). After 16 h, the solvents were removed under reduced pressure and the residue was WO 95102587 WO 9502587PCT/US94/07769 81 purified by pressurized silica gel chromatography using 3:1 hexaneethyl acetate as eluant. The title compound was obtained as a foam from hexane.
Analysis: (C32H5lN307S) caic: C 61.8 1, H 8.27, N 6.76 found: C 61.55, H 8.13, N 6.55 TPC: Rf 0.40 (1:3 EtOAc:hexanes) HPLC (method rentention time 9.71 min '0 FAB MS: m/z 622 +H) 1 H NMR (300 MI-z, CDC13): 867.19 (in, 2H1), 7.02 (in, 2H), 3.66 (s, 6H), 2.31 3H), 1.13 3H), 1.00 (overlapping a and d, 6H).
EXAMPLE 48 1 ,7-dimethyl-2-exo-hydroxy-2-endo-ethenyl-bicyclo(2.2. 1 )heptan- I -vI)methanesulfonfl)-4-(2-methvl-phenyl)-p2iperazine
OH
3
N
<OH
OH
To a -78'C stirred 1.0 M solution of vinyl magnesium chloride in THE (25 mL; 25 mmol) was added a -78'C solution of 1- ((7,7-dimethyl-2-oxo-(2.2. 1) bicycloheptan- 1-yl)methanesulfonyl)-4-(2inethylphenyl)-piperazine (5.00 g; 12.8 inmol) in THF (100 mL) via cannula. The resulting solution was stirred under argon overnight, allowing the cooling bath to warm to ambient temperature The WO 95/02587 WO 9502587PCT1US94/07769 82 reaction was quenched by addition of 2% aqueous HCl (50 mL), and the mixture was partitioned between ethyl acetate and water. The organic phase was washed with aqurous NaHCO3 and brine, dried over MgSO4, and filtered. The solvents were removed under reduced pressure and the residue was purified by pressurized silica gel chromatography using 4:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam from ether.
Analysis: (C23H34N203S) 0.06 caic: C 65.82, H 8.19, N 6.67 found: C 65.99, H 8.42, N 6.63 TLC: Rf 0.36 (1:5 EtOAc:hexanes) HPLC (method rentention time 11.41 min FAB MS: m/z 419 +H) 1H NMR (400 MHz, CDCl3): 5 7.20 (in, 2H1), 7.02 (in, 2H), 6.48 (dd, 1H), 5.30 111), 5.17 1H), 2.32 3H), 1,22 3H1), 0.94 3H).
EXAMPLE 49 J ,7-dimethyl-2-(2-chloro)ethylidinebicyclo-(2.2. I )heptan- I -yl)methanesulfonvl)-4-(2-methyl-p2henvl)-p2iperazine
GH
3
QM
N,
S0 2
CI
To a 0 0 C stirre. solution of 1-((7,7-dimethyl-2-exohydroxy-2-endo-ethenyl-(2.2. I )bicycloheptan- 1 -yl)methanesulfonyl)-4- WO 95/02587 PCT/US94/07769 83 (2-methylphenyl)piperazine (2.90 g; 6.94 mmol) in THF (100 mL) was added triethylamine (1.50 mL; 10.7 mmol) and DMF (0.58 mL; mmol). Thionyl chloride (0.66 mL; 9.1 mmol) was added dropwise, and the resulting solution was stirred for 18 h, allowing the cooling bath to warm ambient temperature. The solvents were removed under reduced pressure and the residue was dissolved in theyl acetate (150 mL) and washed with 5% aqueous HCI (75 mL), water (75 mL) and aqueous NaHCO3 (100 mL). The organic phase was dried (MgSO4).
filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 4:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam.
Analysis: (C23H33C1N202S) 0.6 calc: C 65.82, H 8.19, N 6.67 found: C 65.99, H 8.42, N 6.63 1H NMR (400 MHz, CDC13): 5 7.20 2H), 7.03 2H), 5.87 (m, 1H), 4.10 (ABX, 2H), 2.32 3H), 1.00 3H), 0.82 3H).
EXAMPLE 1-((7,7-dimethyl-2-(2-isobutylamino)ethylidine-bicyclo(2.2.1)heptan-1yl)methanesulfonyl)-4-(2-methylphenvl)-piperazine
CH
3
N
N
2N C -H WO 95/02587 WO 95/02587I'/US94/07769 84 To a stirred solution of 1-((7,7-dimethyl-2-(2-chloro)ethyli dine- 1 )bicycloheptan- I -yI])methane sulfony1) (2-methylIphenyl)peperazmne (200 mg; 0.46 m-mol) in MeOH (2 mL) was added isobutylamine (0.5 mL; 5 mmol). After being stirred fro 18 h, the solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% TFA. The TFA salt of the title compound was obtained as a lyophilized powder.
Anal: (C27H41IN3 02S) 2.0 H20; 1.0 TFA TLC: Rf 0.30 (95:5:0.5 CHC13:MeOH:NH4OH) I-PLC (method rentention time 9.78 min FAB MS: m/z 474 +H) I H NMR (400 MI-z, CD3OD): 8 7.20 (in, 3H), 7.03 1H), 5.78 (in, 1H), 2.35 1.13 J=7 Hz, 6H), 1.12 3H), 0.88 3H).
EXAMPLE 51 201-((7 ,7-dimethyl-2-(2-azido)ethylidine-bilcyclo-(2.2. 1 )heptan- Il-yl)- 20methanesulfonyl)-4-(2-methvl-phenVl)-piperazine O0 H3
N
S0 2
N=N=N
To a stirred solution of 1 ,7-dimethyl-2-exo-hydroxy-2- (2-chl oro)eth yli dine 1 )bicyclo-heptan- I -yl)methanesulfonyl)-4-(2meffiylphenyl)pipereizine (3.58 g;8.19 minol) in DMSO (50 mL) and WO 95/02587 WO 9502587PCT/US94/07769 85 THF (45 mL) was added a solution of sodium azide (5.3 g; 82 mmol) in watr '20 mL). After 24 h, the solvents were removed under reduced pre, the residue was suspended in dichioromethane (100 mL) and washed with water (3 x 50 mL). The organic phase was dried (MgWON), filtered, and the solvent was removed under reduced pressure to give a solid.
Analysis: (C23H33N502S) caic: C 62.27, H 7.50, N 15.79 found: C 62.41, H 7.54, N 15.60 TLC: Rf 0.75 (70:30 hexane-ethyl acetate) HPLC (method rentention time 12.50 min FAB MS: m/z 444 H) I H NMR (300 MI-z, CDCl3): 8 7.20 (in, 2H), 7.02 (in, 2H), 5.79 (in, 1H), 3.78 (ABX, 2H), 2.32 3H), 0.85 3H).
EXAMPLE 52 1 ,7-dimethyl-2-(2-amino)ethylidine-bicyclo-(2.2. 1 )heptan- 1 vi )methanesulfonyl)-4-(2-methylphenvl )-p2iperazine
IMCH
3 S 2 t l
NH
2 To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2- (2-azido)ethylidine-(2.2. 1 )bicyclo-heptan- 1 -yl)methanesulfonyl methylphenyl)piperazine (3.85 g; 8.69 minol) in THF (150 mL) and water (3 mL) was added triphenylphosphine (2.50 g; 9.56 nimol).
WO 95/02587 PCT/US94/07769 86 After 14 h, the solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and extracted with aqueous HCI (3 x 75 mL). The combined acid extracts were washed wtih ethyl acetate (50 mL) and then made basic by adding solid sodium hydroxide to pH 12. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic phases were dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 99:1 to 85:15 chloroform-methanol. The title compound was obtained as a solid.
Analysis: (C23H35N302S) 0.5 calc: C 64.75; H 8.51; N 9.85; found: C 64.59; H 7.51; N 9.71 TLC: Rf 0.56 (95:5:0.5 CHCI3-MeOH-NH40H) HPLC (method retention time 10.38 min FAB MS: m/z 418 H) 1H NMR (CDC13): 'H NMR (300 MHz, CDC13): 87.16 2H), 7.00 2H), 5.61 1H), 3.43 4H), 3.26 J=6.6Hz, 2H), 1.18 (d, J=14.1 Hz, 1HO, 1.97 4H), 2.92 J=14.1 Hz, 1H), 2.35 1H), 2.31 3H), 1.7-1.8 3H), 1.70 1H), 1.25 1H), 0.99 3H), 0.81 3H).
WO 95/02587 WO 9502587PCT/US94/07769 87 EXAMPLE 53 1 ,7-dimethyl-2-(2-(4(5)-imidazolylacetyl)amino)ethylidine-bicyclo- (2.2.1 )heptan- 1 -y)methane-sulfonl)-4-(2-methvlphenvflp1iperazine H 3
N-.
S0 2 0 N
NN
H
To a stirred solution of 1 ,7-dimethyl-2-exo-hydroxy-2- (2-amino)ethylidine-(2.2. 1 )bicyclo-heptan- 1 -yl)methanesulfonyl)-4-(2methylphenyl)piperazine (0.20 g; 0.48 mmol) in DMF (5 mL) was added BOP (265 mg; 0.60 mrnol), 4-imidazoleacetic acid hydrochloride (115 mg; 0.72 mmol) and DIEA (0.38 mL; 2.2 mmol). After 14 h, the solvents were removed under reduced pressure, the residue was suspended ini ethyl acetate (50 mL) and washed with aqueous NaHCO3 (2 x 25 mL) and water (2 x 25 mL). The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure.
The residue was purified by preparative reverse phase HPCL using an acetonitrile-water gradient containing 0. 1 TFA. The TFA salt of the title compound was obtained as a lyophilized powder.
Analysis: (C28H39N503S); 0.5 H20; 2.0 TFA; caic: C 50.38; H 5.55; N 9. 18 found: C 50.40; H 5.55; N 9.40 TLC: Rf 0.42 (95:5:0.5 CHCI3-MeOH-NH4OH) HPLC (method retention time 8.76 min.
FAB MS: m/z 526 +H) WO 95/02587 PCT/US94/07769 -88 1H NMR (400 MHz, CDC13): 6 8.40 1H), 7.58 (br m, 1H), 7.22 (m, 3H), 7.10 2H), 5.57 (br t, 1H), 2.37 3H), 0.97 3H), 0.76 (s, 3H).
EXAMPLE 54 1-((7,7-Dimethyl-2-spiro-epoxy-bicyclo(2.2.1)heptan- -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine
N
so 2 To a stirred 0°C suspension of trimethyl-sulfoxonium iodide (6.78 g; 30.8 mmol) in THF (100 mL) was added n-butyllithium (11.1 mL of a 2.5 M solution in hexane; 27.7 mmol). After 4 h at 0°C, a solution of 1-((7,7-dimethyl-2-oxo-(2.2.1)bicyclo-heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (8.00 g; 20.5 mmol) in THF (50 mL). The resulting solution was stirred at 0°C for 2 h, and then at ambient temperature for 18 h. The solvents were removed under reduced pressure, the residue was dissolved in ethyl acetate (150 mL) and washed with water (2 x 50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The resulting solid was recrystallized from ether to give the title compound as white needles, mp 131-133 0
C.
WO 95/02587 WO 95/02587PCT 1US94 /077 69 89 Analysis: (C22H32N202S) caic. C, 65.31; H, 7.97; N, 6.92 found C, 65.09; H, 7.99; N, 6.86 TLC: Rf 0.62 (4:1 hexane-ethyl acetate) HPLC (method retention time 11.50 min FAB MS: m/z405 +H) I H NMR (300 MHz, CDCI3): 6 7.20 (in, 2H), 7.02 (mn, 2H), 3.20 (d, J=5.4 Hz, 1H), 2.70 J=5.4 Hz, 1H), 2.30 3H), 1.00 3H), 0.99 3H).
EXAMPLE 1 ,7-Dimethyl-2-exo-hydroxy-2-endo-isobutylamino-methylbicyclo(2.2. 1)heptan- 1-yl)methanesulfonyl )-4-(2-methylphenyl)pip erazine
OH
3 Q
N
N
OH0-
HN
OH
3
OH
3 To a stirred solution of 1-((7,7-dimethyl-2-(spiroepoxy)- (2.2.1 )bicycloheptan- 1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mng; 0.495 rrmol) in MeOH (3 mE) was added isobutylainine (0.5 mL; 5 minol). After being stirred for 18 h, the WO 95/02587 WO 9502587PCI'/US94/07769 90 solvents were removed under reduced pressure and the residue was purified by pressurized silica gel coliumn chromatography using 98:2:0.2 chloroformn-methanol-NH4OH as eluant. The product was dissolved in methanol and to it was added several drops of 5% aqueous HCl. The solvents were removed under reduced pressure and the residue was triturated in ether to give the hydrochloride salt of the title compound as a white powder.
Analysis: (C26H43N303S) calc. C, 57.00; H, 8.76; N, 7.67 found C, 57.03; H, 8.84; N, 7.61 HCl, 1.8 TLC (free base): Rf 0.20 (3:1 hexa-ne-ethyl acetate) HPLC (method retention time 9.54 min FAB MS: m/z478
+H)
I H NMR (300 MHz, CDCl3): 8 7.20 (in, 2H), 7.02 (mn, 2H), 2.30 (s, 3H), 1.1,0 3H), 0.95 3H), 0.90 (two doublets, 6H).
EXAMPLE 56 1 ,7-Dimethyl-2- methoxycarbonyl-bicyclo(2.2. 1)hept-2-en- 1vi )methanesulfonyfl-4-(2-methviphenvI '-piperazine
OH
3 0 N~
N
S0 2 00 2
CH
3 To a stirred, 0 0 C solution of 1 ,7-dimethyl-2-oxobi cyclo 1 )hep tan- I -yl)methanes ulfony l)-4 -(2-methylIphenylI)piperazine (10.0 g; 25.6 mmol) in dichloromethane (500 mL) was added WO 95/02587 PCT/US94/07769 -91 2,6-di-t-butyl-4-methylpyridine (7.8 g; 38 mmol) and trifluoromethanesulfonic anhydride (5.4 mL; 32 mmol). The cooling bath was removed and the solution was stirred for 18 h. The mixture was filtered and the filtrate was washed with 5% aqueous HCI (2 x 100 mL), water (100 mL), and aqueous NaHCO3 (2 x 100 mL). The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure.
The residue was purified by pressurized silica gel column chromatography using 9:1 hexane-ethyl acetate as eluant. The en'! triflate product was obtained as a white foam and used as such in the next step. To a stirred solution of 1-((7,7-dimethyl-2-trifluoromethanesulfonyloxy-bicyclo(2.2. 1)-hep-2-en- -yl)methane-sulfonyl)-4- (2-methylphenyl)-piperazine (10.5 g; 20.1 mmol) in 1:1 DMF-MeOH (150 mL) was added triethylamine (5.9 mL; 43 mmol), triphenylphosphine (317 mg; 1.21 mmol), and palladium(II)acetate (135 mg; 0.603 mmol). Carbon monoxide gas was bubbled through the solution for 15 min, and the reaction was kept under atmospheric pressure of CO for 18 h. The solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 9:1 hexane-ethyl acetate as eluant. The title cumpound was obtained as a white foam from hexane.
Analysis: (C23H32N204S) calc. C, 62.14; H, 7.50; N 6.30 found C, 61.65; H, 7.17; N, 6.12 0.67 TLC: Rf 0.36 (1:5 EtOAc:hexanes) HPLC (method retention time 11.34 min FAB MS: m/z 433 H) 1 H NMR (400 MHz, CDC13): 6 7.20 2H), 7.03 2H), 6.88 (d, J=3 Hz, 1H), 3.72 3H), 2.33 3H), 1.09 3H), 1.01 3H).
I I WO 95/02587 WO 5/0587PCT /IS94/07769 92 EXAMPLE 57 I -((7,7-Dirmethyl-2-carboxy-bicyclo(2.2. 1 )hept-2-en- I -yI)methaniesulfonyl)-.4-(2-methylphienyflp1iperazine C H 3 0
N
N S02 C0 2
H
To a stirred solution of 1-((7,7-dimethyl-2-methoxycarbonyl-bicyclo(2.2. 1 )hept-2-en- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (1.0 g; 2.3 mmnol) in MeOH (10 mL) was added a solution of 4 M aqueous KOH (2.0 m.L; 8.0 mmnol). After 18 h, the reactior ias brought to pH 1 with 5% aqueous HCl, and the solvents were i moved under reduced pressure. The residue was taken up in chloroform (50 mL) and washed with water (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the hydrochloride salt of the title compound as a white foamn.
Analysis: (C22H30N204S) caic. C, 57.5 1; H, 6.9 1; N, 6. found C, 57.40; H, 6.87; N, 6.01 1.0 HC1, 0.25 1120 TPC: Rf 0.59 (92:8:0.1) CHCI3:MeOH:HOAc) HPLC (method retention time 9.77 min FAB MS: m/z419 +H) I H NMR (400 MHz, CD3OD): 8 7.30 (in, 3H), 7.20 111), 6.89 (d, J=3 Hz, I 2.43 1.11(s, 3H), 1.00 3H).
WO 95/02587 WO 9502587PCI/US94/07769 93 EXAMPLE 58 1 ,7-Dimethiyl-2-(4-imidazolyl)ethylaminocarbonyl-bicyclo( 2 2 1)hep~t-2-en- 1 -v)methanesulfonvl )-4-(2-methvlp~henylpiperazine IM H 3
N,
N 02-
N
1
N
H
To a stirred solution of 1-((7,7-dimethyl-2-carboxybicyclo- (2.2.1 )hept-2-en- 1 -ylmethanesulfonyl)-4-(2-methylpheny1)piperazine (100 mg; FW=460; 0.22 mmol) in DMF (5 ml-) was added histamine mg; 0.27 mmol), BOP (115 mg; 0.25 mmol) and DIFA 12 mL; 0.69 mmol). After 18 h, the solvent was removed under reduced pressure, the residue was purified by preparative reverse phase 1HPLC using an acetonitrile-water gradient containing 0.1% ThA. The TFA salt of the title compound was obtained as a lyophilized powder.
Analysis: (C27H37N503S) ca1c C, 49.35; H, 5.3 1; N, 9.22 found C, 49.25; H, 5.39; N, 9.20 2.1 TFA, 0.45 HPLC (method retention time 8. 16 min FAB MS: m/z512 +H)
I
WO 95/02587 PCT/US94/07769 -94- 1H NMR (300 MHz, CD30D): 8 8.80 1H), 7.40 1H), 7.18 (m, 2H), 7.05 1H), 6.99 1H), 6.41 J=3 Hz, 1H), 2.31 3H), 1.08 3H), 0.98 3H) EXAMPLE 59 1-((7,7-Dimethyl-2-endo-methoxycarbonyl-bicyclo-(2.2.1)heptan-1vl)methanesulfonyl)-4-(2-methyl-phenyl)piperazine
CH
3
N
SO2
SH
CO
2
CH
3 To a stirred, -78 0 C solution of l-((7,7-dimethyl-2methoxy-carbonyl-bicyclo(2.2.1 )hept-2-en-1 -yl)methanesulfonyl)-4-(2methyl-phenyl)piperazine (3.0 g; 6.9 mmol) in 2:1 THF-MeOH (50 mL) was added a solution of 0.1 M samarium(II) iodide in THF (250.0 mL; 25.0 mmol). After 1 h, the reaction was warmed to ambient temperature and stirred for another 1 h. The solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The layers were separated and the organic phase was washed with water (50 mL), dried (MgSO4), filtered, and evaporated to dryness under reduced pressure. By 1H NMR analysis, a 6:1 ratio of endo:exo products was obtained. The major, lower Rf isomer (endo) was obtained in pure form by pressurized silica gel column chromatography using a gradient elution of 98:2 to 95:5 hexane-ethyl acetate, followed by crystallization from
IL--
WO 95/02587 WO 95/2587 cT/US94/07769 95 ethyl acetate. The title compound was obtained as white needles, mp 156-158 0
C.
Analysis: (C23H34IN204S) caic. C, 63.56; H, 7.89; N, 6.45 found C, 63.31; H, 7.83; N, 6.43 TLC: Rf =,0.44 (1:5 EtOAc:hexanes) HPLC (method retention time 11.75 min FAB MS: m/z 435 +H) 1 H NMR (400 MI-z, CDC13): 8 7.20 (in, 2H), 7.05 (in, 2H), 3.72 (s, 3H), 3.29 (ddd, 1H), 2.34 3H), 1.13 3H), 1.06 3H).
EXAMPLE -((7.7-Diinmethyl-2-endo-carboxy-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenvl~piperazine
OH
3
QM
N
C0 2
H
To a stirred solution of 1 ,7-dimethyl.-2-endo-methoxycarbonyl-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl )-4-(2-methylphenyl)piperazine (1.0 g; 2.3 rnmol) in TI-F (10 mL) was added a solution of 4 M aqueous NaGH (1.5 mL; 6.0 mmol). The reaction was heated to reflux for 72 h, cooled, arnd brought to pH 1 with 5% aqueous HCI. The solvents were removed under reduced pressure and the residue was partitioned between chloroform and water. The organic phase was separated and washed with water, dried (MgON), filtered, WO 95/02587 WO 95/2587 C/US94/07769 96 and the solvent was removed under reduced pressure. The title compound was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% TFA. The title compound was obtained as a lyophilized powder.
Analysis: (C22H32N204S) caic. C, 51.92; H, 5.99; N, 4.94 found C, 51.92; H, 5.95; N, 5.17 1.25 TFA, 0.2 TLC: Rf 0.22 (95:5:0.5 CHCI3:MeOH:NI140H) HPLC (method retention time 10.67 min FAB MS: m/z421 +H) IH NMR (300 MHz, CD3OD): 8 7.18 (in, 2H), 7.05 1H), 6.98 (t, IR), 2.30 3H), 1.18 3H), 1.10 3H).
EXAMPLE 61 1 -((7,7-Dmty -no(-iiaoy~tyain-abnlbcco (2.2.1 )heptan-I1-yI)methanesulfonyl')-4-(2-methylp~henyl)p2iperazine
CH
3
ON
O N__ WO 95/02587 WO 9502587PCT/US94/07769 97 To a stirred solution of 1-((7,7-dimethyl-2-endo-carboxybicyclo(2.2. 1 )heptan-1I -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg; 0.238 mmol) in DMF (5 mL) was histamine mg; 0.32 mmol), BOP (142 mg; 0.32 1 mmol), and DIBA (0.13 mL; 0.75 mmol'. After 18 h, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1 TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C27H39N503S) caic. C, 46.66; H, 5.58; N, 8.58 found C, 46.63; H, 5.23; N, 8.97 2.35 TFA, 1.9 HPLC (method retention time 8.99 min FAB MS: m/z514 +H) IH NMR (300 MI-z, CDCl3): 8 8.40 1H), 7.1-7.3 (in, 5H1), 2.39 (s, 3H), 1.05 3H), 0.98 3H).
EXAMPLE 62 Two isomers of 1 ,7-dimethyl-2-exo-hydroxy-2-endo-2-( 1-(3methoxycarbonyl)-2-pyrrolidinon- I -yl)propylbicyclo-(2.2. 1 )heptan- I vI')methanesulfonyl)-4-(2-methlphenyDvLe-iprazinle WO 95/02587 WO 9502587PCT/US94107769 98
IMCH
3
N.
SO
2
OH
100 00 2
CH
3 To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2endo-2-( I -amino)propyl-(2.2. 1 )bicyclo-heptan- 1 -yl)methanesulfonyl)-4- (2-methylphenyl)piperazine (250 mg; 0.557 minol) in methanol (3 mL) was added dimethyl itaconate (200 mg; 1.27 mmol). The reaction was heated to refiux for 18 h. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 35:65 hexane-ethyl acetate as eluant. The products were obtained as white foams.
Isomer 1: Analysis: (C30H-45N306S) calc. C, 62.58; 7.88; N, 7.30 found C, 62.58; H, 8.03; N, 6.95 TLC: Rf 0.34 (35:65 hexane-ethyl acetate) HPLC (method retention time 10.23 min FAB MS: m/z 576
+H)
I H NMR (300 MI-z, CDC13): 8 7.18 (in, 2H), 7.01 (in, 2H), 3.76 (s, 3H), 2.32 3H), 1.15 3H), 1.03 3H), 0.95 J=6 Hz, 311).
WO 95/02587 WO 9502587PCI'/US94/07769 -99 Isomer 2: Analysis: (C30H45N306S) caic. C, 62.58; H, 7.88; N, 7.30 found C, 62.43; H, 8.07; N, 6.95 TLC: Rf 0.23 (35:65 heaxane-ethyl acetate) HPLC (method retention time 10.24 min FAB MS: m/z 576 H) I H NMR (300 MHz, CDCl3): 5 7.20 (in, 2H), 7.03 (mn, 2H), 3.74 (s, 3H), 2.32 3H), 1.15 3H), 1.03 3H), 0.95 J=6 Hz, 3H).
EXAMPLE 63 1 -((7,7-Diinethyl-2-exo-hydroxy-2-endo-2-( 1-(4-pyridinyl)methylamino)-propyl-bicyclo(2.2. 1 )heptan- 1 -yi )methanesulfonyl)-4-(2methvlp~heny D-p2iperazine
OH
3
QNN
200 OH, NHJ To a stirred solution of 1-((7,7-dii-w, yl-2-exo-hydroxy-2endo-2-( 1 -amin o)p ropyl1-(2.2. 1 )bicycloheptan- t-yl)methanesulfonyl)-4- (2-methyl-phenyl)piperazine (50 mg; 0. i 1 rr- riol) in DMF (2 mL) was added 4-chioro-methylpyridie hydrochlo!r4de (18 mg; 0. 11 minol) and potassium carbonate (50 mg; 0.36 mmo', The reaction was heated to 18 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an WO 95/02587 WO 9502587PCIT1US94/07769 100 acetonitrile-water gradient containing 0. 1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C30H44N403S) caic. C, 52.07; H, 5.89; N, 7.06 found C, 52.06; H, 5.86; N, 7.20 2.2 TFA, 0. 1 TLC: Rf 0.36 (95:5:0.5 CHCl3:MeOH:NI-40H) HPLC (method retention time 8.15 min '0 FAB MS: m/z 541 +H) I H NMR (300 MI-z, CDCI3): 5 8.72 (br s, 2H), 7.85 (br s, 2H), 7.20 (in, 2H), 7.03 (in, 2H), 4.27 (AB quartet, 2H), 2.31 3H), 1.14 (s, 3H), 0.95 (overlapping s and d, 6H).
EXAMPLE 64 1 ,7-Dimethy1- 2-(Q3-acetamnido 3,3 '-di (eth ox ycarbonyl1))p ropy li dinebicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)p2iperazine N S. 2 0
~H
N OH 3 0H 3
CH
2 0 2 0 00 2 0H 2
CH
3 To a stirred solution of diethyl acetamidomalonate (0.69 g; 3.2 minol) in DMF (20 rnL) was added NaH (125 mng of a dispersion in mineral oil;, 3.13 mrnol). After 30 min, 1-((7,7-dimethyl- WO 95/02587 WO 95/2587 C'I'/US94/07769 101 2-(2-chloro)-ethyli dine 1 )bicycloheptan- I -yl)methanesulfoniyl)-4- (2-methylphenyl)-piperazine (0.35 g; 0.80 rnmol) was added and the mixture was warmed to 50'C for 3 h. The mixture was cooled and acetic acid (1.5 mL) was added. The solvents were removed under reduced pressure, the residue was dissolved in ethyl acetate (75 mL) and washed with water (3 x 25 mL). 'I e organic phase was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized qilica gel column chromatography using 2:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam.
Analysis: (C32H47N307S) calc. C, 62.32; H, 7.51; N, 6.81 found C, 61.96; H, 7.7 1; N, 6.55 TLC: Rf 0.36 (95:5:0.5 CHCI3:MeOH:NI-40H) I-PLC (method retention time 1.1.54 min FAB MS: m/z618 +H) I H NMR (400 Mlz, CDCl3): 8 7.20 (in, 2H), 7.03 (in, 2H1), 6.78 (s, 1H1), 5.38 (br t, 1H), 4.22 (in, 4H), 2.32 3H), 2.00 1.27 (t, J=7 Hiz, 3H), 1.24 J=7 Hz, 3H), 0.97 3H), 0.78 3H).
EXAMPLE 1 ,7-Dimethy 1-2-(3-acetamido-3-carboxy)propylidine-bicyclo- (2.2.1 )-heptan- 1 -vl)methanesulfonvl)-4-(2-methvlplienvl)piperazine WO 95/02587 PCT/US94/07769 102- C H 3 [D N
N
SO
2
CO
2
H
H
3 C NH 0 To a stirred solution of 1-((7,7-dimethyl-2-(3-acetamido- 3,3'-di(ethoxycarbonyl))propylidine-(2.2.1 )bicycloheptan- -yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (0.10 g; 0.16 mmol) in ethanol (2 mL) was added a solution of 2 M NaOH (0.30 mL; 0.60 mmol) and the mixture was heated to reflux for 6 h. The mixture was cooled and brought to pH 2 with 5% aqueous HCI. The mixture was heated to reflux for 1 h. The solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The title compound, as a 1:1 mixture of diastereomers, was obtained as a lyophilized powder.
Analysis: (C27H39N305S) calc. C, 54.37; H, 6.53, N, 6.56 found C. 54.26; H, 6.41; N, 6.59 TFA, 0.5 TLC: Rf 0.39 (92:8:0.1 CHCI3:MeOH:HOAc) HPLC (method retention time 9.62 min FAB MS: m/z518 IH NMR (400 MHz, CDC13): 8 7.25 4H), 7.13 4H), 6.52 (d, 1H), 6.40 1H), 5.45 1H), 5.40 1H), 4.67 2H), 2.40 (s, 6H), 20.5 3H), 2.04 3H), 1.01 3H), 0.98 3H), 0.88 3H), 0.79 3H).
WO 95/02587 PCT/US94/07769 103 EXAMPLE 66 1-((7,7-Dimethyl-2-oxo-bicyclo(2.2.1)heptan- -yl)methanesulfonyl)-4- (2-methylphenyl)-3-piperazinone
CH
3
N"
O N S O 2 0 To a stirred solution of l-t-butyloxycarbonyl-4-(2-methylphenyl)-3-piperazinone (0.25 g; 0.86 mmo!) in dichloromethane (3 mL) was added TFA (1 mL). After 1 hour the solvents were removed under reduced pressure and the residue was taken up into chloroform and 0evaporated several times to remove excess TFA. The residue was dissolved in chloroform (5 mL) and added to the stirred solution was chloride (376 mg; 1.50 mmol) and triethylamine (0.38 mL; 2.7 mmol). After 12 hours, the mixtire was diluted with chloroform (25 mL) and extracted with 5% aqu us HCI (25 mL), water (25 mL), and aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 2:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam from ether-hexane.
Analysis: (C21H28N204S) calc. C, 62.35; H, 6.98; N, 6.93 found C, 61.78; H, 6.98; N, 6.82 TLC: Rf 0.30 (1:1 hexane-ethyl acetate) WO 95/02587 PCTIUS94/07769 104- HPLC (method retention time 8.15 min FAB MS: m/z 405 H) EXAMPLE 67 1 -((7,7-Dimethyl-2-oxo-bicyclo(2.2.1 )heptan-1 -yl)-methanesulfonyl)- 4-(2-methylphenyl)-2-methyl-3-piperazinone o CH 3
I
CH
3 0 To a stirred 78 0 C solution of LDA (2.0 mmol) in THF mL) was added a -78°C solution of 1-t-butyloxycarbonyl-4-(2-methylphenyl)-3-piperazinone (0.50 g; 1.7 mmol) in THF (5 mL). The resulting solution was stirred for 1 hour, when iodomethane (0.125 mL; mmol) was added. The reaction mixture was stirred at -78 0 C for minutes, and then the cooling bath was removed and the mixture was stirred at ambient temperature for 3 hours. Water (10 mL) and ethyl 2 acetate (50 mL) were added. The organic layer was separated and washed with water (25 mL) and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 85:15 hexane-ethyl acetate as eluant. The methylated product had an Rf 0.47 (70:30 hexane-ethyl acetate) and an HPLC retention time of 8.32 min (Method The product (0.40 g; 1.3 mmol) was dissolved in chloroform (3 mL) and TFA (1 mL) was added. After 2 hours, the mixture was diluted with chloroform mL) and extracted with aqueous NaHCO3 (3 x 25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under L I-I WO 95/02587 PCT/US94/07769 105reduced pressure to give an oil (HPLC retention time 2.95 min, Method The residue was dissolved in chloroform (20 mL) and to the stirred solution was added 10-camphorsulfonyl chloride (0.41 g; 1.6 mmol) and triethylamine (0.28 mL; 2.0 mmol). After 12 hours, the mixture was diluted with chloroform (25 mL) and extracted with 5% aqueous HCI mL), water (25 mL), and aqueous NaHCO3 (2 x 25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 2:1 hexane-ethyl acetate as eluant. The title compound, as a 1:1 mixture of diastereomers, was obtaried as a white solid from hexane-ether.
Analysis: (C22H30N204S) calc. C, 63.13; H, 7.23; N, 6.69 found C, 63.46; H, 7.09; N, 6.74 TLC: Rf 0.27 (60:40 hexane-ethyl acetate) HPLC (method retention time 8.52 min FAB MS: m/z 419 (M H) 1 H NMR (300 MHz, CDC13): 5 7.1-7.3 8H), 4.62 (overlapping quartets, 2H), 2.21 3H), 2.20 3H), 1.68 (overlapping doublets, 6H), 1.13 3H), 1.11 3H), 0.91 3H), 0.89 3H).
EXAMPLE 68 1-((7,7-Dimethyl-2-exo-hydroxy-bicyclo(2.2.1 )heptan-1 -yl)methanesulfonvl)-4-12-methylphenvl)-2-methvl-piperazine
C
H
3 30 N.
WO 95/02587 PCT/US94/07769 106- To a stirred, 0 C solution of -((7,7-dimethyl-2-oxobicyclo(2.2.1 )heptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)-2methyl-3-piperazinone (0.15 g; 0.36 mmol) in THF (5 mL) was added a M solution of LAH in THF (1.1 mL; 1.1 mmol). The resulting solution was warmed to ambient temperature and stirred for 3 hours.
The reaction was quenched by adding aqueous NaOH to give a white precipitate. The mixture was diluted with ethyl acetate and the solids were removed by filtration through Celite. The filtrate solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 9:1 hexane-ethyl acetate as eluant to give 1-((7,7-dimethyl-2-exo-hydroxy-bicyclo- (2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl)-2-methyl-2,3dehydro-piperazine (FAB MS: m/z 405 olefinic proton at 5.8 ppm ,n the 1 H NMR spectrum). This product (75 mg; 0.19 mmol) was dissolved in triethylsilane (2 mL) and to the stirred solution was added TFA (0.030 mL; 0.38 mmol). After 18 hours, the solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate (20 mL) and washed with aqueous NaHCO3 (2 x 10 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The title compound, as a 1:1 mixture of diastereomers, was obtained as a lyophilized powder.
HPLC (method retention time 14.33 min FAB MS: m/z 407 H) 1 H NMR (400 MHz, CDC13): 8 7.20 4H), 7.06 4H), 4.20 (m, 2H), 2.36 6H), 1.55 (overlapping doublets, 6H), 1.09 6H), 0.86 (s, 6H).
I
WO 95/02587 PCT/US94/07769 107- EXAMPLE 69 1-((7,7-Dimethyl-2-oximino-bicyclo(2.2.1 )heptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine NS 2
SO
2
N
OH
To a stirred solution of 1-((7,7-dimethyl-2-oxo-bicyclo- (2.2.1 )-heptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (65.0 g; 166 mmol) in pyridine (250 mL) was added hydroxylamine hydrochloride (35.0 g; 0.504 mol). The solution was heated to 70 0 C for 18 h. The solvent was removed under reduced pressure, the residue was taken up in chloroform (500 mL) and washed with aqueous NaHCO3 (2 x 200 mL), water (100 mL), and 5% aqueous HC1 (2 x 200 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The title compound crystallized from ethyl acetate, giving off-white needles (57 g; mp 174- 175 0
C.
Analysis: (C21H31N303S) calc. C, 62.19; H, 7.71; N, 10.36 found C, 62.29; H, 7.63; N, 10.15 TLC: Rf 0.40 (75:25 hexane-ethyl acetate) HPLC (method retention time 9.98 min FAB MS: m/z 406 H)
M
WO 95/02587 PCT/US94/07769 108- 1H NMR (300 MHz, CDC13): 6 7.90 (br s, 1H), 7.18 2H), 7.02 (m, 2H), 3.47 4H), 4.43 J=14.4 Hz, 1H), 3.00 4H), 2.92 (d, J=14.4 Hz, 1H), 2.4-2.6 2H), 2.31 3H), 2.09 J=16.9 Hz, 1H), 1.95 2H), 1.80 1H), 1.32 1H), 1.08 3H), 0.87 3H).
EXAMPLE 1-((7,7-Dimethyl-2-endo-amino-bicyclo(2.2.1)heptan-1-yl)methane- 1 sulfonvl)-4-(2-methylphenyl)-piperazine MCH 3
N.
SO
2
H
2
N
To a stirred solution of 1-((7,7-dimethyl-2-oximinobicyclo(2.2.1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (35.0 g; 86 mmol) in 2-methoxyethanol (500 mL) containing Raney Nickel alloy (105.0 g) was added sodium hydroxide solution (17.2 g; 430 mmol dissolved in 75 mL) dropwise over 30 min. During the addition heat and gas was evolved. The mixture was stirred at ambient temperature for 16 h, at which time TLC indicated complete consumption of starting oxime and a ca. 4:1 mixture of endo (lower Rf) and exo (higher Rf) amine products. The mixture was filtered through Celite and the filtercake was washed with methanol and ethyl acetate. The solvents were removed under reduced pressure and the resulting solid was dispersed in water and filtered. The dried solid was purified by pressurized silica gel column chromatography, using a 93:3 to 94:6 A:B gradient elution (A=chloroform, B=5% The title compound was obtained as a white foam (24 g; FAB MS: m/z 392 H).
WO 95102587 PCT/US94/07769 109- EXAMPLE 71 1-((7,7-Dimeth yl-2-endo-(2S-(tert-butyloxycarbonyl-amino)-4-(methylsulfonyl)-butyrtunido)-bicyclo(2.2.1)-heptan-1-yl)methanesulfonyl)-4- (2-methylphenvl)-piperazine
CH,
N
N,
SO2
HN
S0 2
CH
HN O 0 To a stirred solution of 1-((7,7-dimethyl-2-endo-aminobicyclo(2.2. 1)heptan-1 -yl)methanesulfonyl)-4-(2-methylpheniyl)piperazine (2.0 g; 5.1 mmol) in DMF (20 mL) was added Boc-Lmethionine sulfone (1.5 g; 5.3 mmol), BOP reagent (2.5 g; 5.6 mmol), followed by DIEA (1.85 mL; 10.6 mmol). After being stirred at ambinet temperature for I h, more DIEA (ca. 0.1 mL) was added to obtain a pH 8 solution. The solution was stirred for another I h, when the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with 5% aqueous HCL (2 x 50 mL), water (2 x 50 mL), and aqueous NaHCO3 (2 x 75 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography, using 4:1 EtOAchexanes as eluant. The title compound was obtained as a solid from methanol (2.8 g; WO 95/02587 WO 9502587PCT/US94/07769 110- Analysis: (C3 1 H50N407S2) caic. C, 55.78; H, 7.76; N, 8.39 0.7-H20 found C, 55.57; H, 7.70; N, 8.36 TLC: Rf 0.73 (95:5 CHCl3:MeOH) HPLC (method retention time 11.02 min FAB MS: m/z 655 +H) I H NMR (300 MHz, CDCl3): 5 7.19 (in, 2H), 7.04 (mn, 2H), 5.38 (br d, 1H), 4.32 J=7.4 Hz, 1H), 4.22 (mn, 1H), 2.94 3H), 2.32 3H), 1.45 9H), 1.00 3H), 0.98 3H).
EXAMPLE 72 1 ,7-Dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)-butyramido)bicyclo(2.2.I1)heptk!,n- 1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine- Oo H 3
N
N~s S02
HIN
0 SO 2
CH
3 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2S-tertbutyloxycarbonylamino-4-(inethylsulfonyl)-butyrainido)-bicyclo(2.2. 1)heptan- 1-yl)inethane sulfonyl)-4-(2-methylphenyl)piperazine (2.5 g; 3.8 inmol) in dichloroinethane (15 mEL) was added TFA (5 mE). After 1 h, the solvents were removed under reduced pressure.The residue wa~l dissolved in chloroform (100 inL) and washed with aqueous NaHCO3 (2 x 75 mE). The organic phase was dried (MgSO4), filtered, and the WO 95/02587 WO 9502587PCTJUS94/07769 -111Isolvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 95:5:0.5 CHCl3:MeOH:NI-40H as eluant. The title was obtained as a white foam from EtOAc (1.9 g; Analysis (C26H42N405S2) caic. C, 56.14; H, 7.75; N, 9.29 0.55 EtOAc found C, 55.94; H, 7.74; N, 9.31 TLC: Rf 0.17 (95:5:0.5 CHC13:MeOH:N7H4OH) HPLC (method retention time 8.50 min FAB MS: m/z455 (M H) IH NMR (300 MI-z, CDCl3): 5 7.67 J=8.4 Hz, 1H), 7.20 (in, 2H), 7.02 4.43 (in, 1H), 2.94 3H), 2.31 3H), 1.03 3H), 0.97 3H).
EXAMPLE 73 1 ,7-Dimethyl-2-endo-(2S-(imidazol-4-ylacetyl-amino)-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1 )-heptan- 1 -yl)methanesulfonyl)-4-(2mnethyl pheny 1) -piperazine NoHN S0 2 0H 3 WO 95/02587 PCT/US94/07769 112- To a stirred solution of l-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1)heptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazinc (250 mg; 0.45 mmol) in DMF (5 mL) was added 4-imidazole acetic acid hydrochloride (110 mg; 0.68 mmol), BOP (265 mg; 0.60 mmol), and DIEA (0.355 mL; mmol). The solution was stirrred at ambient temperature for 18 h.
The solvent was removed under reduced pressure, and the residue was suspended in EtOAc (100 mL) and filtered through Celite to remove red polymer. The filtrate was washed with 5% aqueous HCI (50 mL), water (50 mL), and aqueous NaHCO3 (2 x 50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8:0.8 CHCI3:MeOH:NH40H as eluant.
The title compound was obtained as a solid from EtOAc (230 mg; 78%).
Analysis: (C31H46N606S2) calc. C, 53.74; H, 7.32; N, 11.26 0.6 EtOAc, 1.7H20 found C, 53.74; H, 7.00; N, 11.25 TLC: Rf 0.22 (90:10:0.5 CHCI3:MeOH:NH40H) HPLC (method retention time 8.49 min FAB MS: m/z 663 H) 1 H NMR (300 MHz, CDC13): 8 7.73 (overlapping singlet and broad singlet, 2H), 7.38 (br d, 1H, 7.18 2H), 7.02 2H), 6.96 1H), 4.68 (br q, J ca. 5 Hz, 1H), 4.27 1H), 3.62 (br s, 2H), 2.92 (s, 3H), 2.30 3H), 1.00 3H), 0.98 3H).
WO 95/02587 WO 9502587PCT1US94/07769 113 EXAMPLE 74 1 ,7-Dimethyl-2-endo-(2S-(dimethylamino)-4-(methiylsulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenvl)piperazine ao H 3
N
NS
HN H 0CH 3 o 'H OH 3
SO
2
CH
3 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyramido)-bicyclo-(2.2. 1 )-heptan- I1yI)methanesulfonyl)-4-(2-methylpheniyl )-piperazine (250 mg; 0.45 mmol) in 1: 1 HOAc:MeOH (10 mL) was added 37 aqueous formaldehyde (2 mL) and NaBH3CN (60 mg; 0.95 mmol). The solution was stirred at ambient temperature for 4 h. Aqueous NaH-C03 (2 mL) was added and the solvents were removed under reduced pressure. The residue was suspended in EtOAc (75 mL) and washed with water (2 x 50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The title was obtained as a white foam from EtOAc (190 mg; 72%).
Analysis: (C28H46N405S2) calc. C, 57.56; H, 8.01; N, 9.200.3 EtOAc, found C, 57.41; H, 7.98; N, 9.20 WO 95/02587 WO 9502587PCT1US94/07769 114 TLC: Rf 0.26 (95:5:0.5 CHC13 HPLC (method retention time 9. 10 min FAB MS: m/z 583 +H) IH NMR (400 MHz, CDCI3): 5 7.62 (Br s, 1H), 7.18 (in, 2H), 7.02 (M, 2H), 4.37 (in, 1H), 2.92 3H), 2.36 6H), 2.30 3H), 1.02 3H), 0.98 3H), EXAMPLE 1 ,7 -Dimethyl1-2 -endo-benzylIoxycarbon yl amino -b icyc Io 1)hep~tan- 1 -vl)methanesulfonyl )-4-(2-methvl -phenyl)-p2iperazine
OH
3
N
0NN HN H To a 0 0 C stirred solution of 1-((7,7-dimethyl-2-endo- 25amino-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (1.20 g; 3.07 mmol) in CHC13 (100 mL) was added DIEA (0.80 mL; 4.6 mmol) and benzyl chioroformate (0.58 g; 3.4 inmol). The solution was stirred at 0 0 C for 1 h and then at ambient temperature for 4 h. The reaction mixture was washed with aqueous HCI (2 x 50 mL) and aqueous NaHC03 (100 The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc-hexanes as eluant. The title compound was obtained as a white foam. (1.45 g; WO 95/02587 WO 9502587PCT/US94/07769 115 Analysis: (C29H39N304S) caic. C, 65.75; H, 7.5 3; N, 7.77 0.15 EtOAc, 0. 1 found C, 65.90; H, 7.49; N, 7.80 TLC: Rf 0.38 (1:3 EtOAc:hexanes) HPLC (method retention time 12.18 min FAB MS: m/z 526 EXAMPLE 76 1 -((7,'7-DimethylI-2-en do-methylI(benzy lox y -carbony1) amino -bi cyc lo (2.2.1 )-heptan- I -vl)methaniesulfonvl )4-(2-methvlpheniyl)piperazine
CH
3 a
H
3 0C-N H To a 0 0 C stirred solution of 1-((7,7-dimethyl-2-endobenzyloxycarbonylamino-bicyclo(2.2. 1)-heptan- 1-yl)methaniesulfonyl)- 4-(2-methylphenyl)-piperazine (1.46 g; 2.78 mmnol) in DMF (20 mL) was added iodomethane (0.435 nIL; 7.00 m-mol) and sodium hydride (0.139 mg of a 60% dispersion in mineral oil; 3.48 mmol). The was stirrred at 0 0 C for I h and then at ambient temperature for 18 h. The reaction mixture was treated with HOAc (I mL) and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aqueous NaHCO3 (2 x mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified WO 95/02587 WO 95/2587 C'I'/US94/07769 116 by pressurized silica gel column chromatography using 1:5 EtOAchexanes as eluant. The title compound was obtained as a white foam.
(1.40 g; 93%).
Analysis: (C30H4iIN304S) calc. C, 66.03; H, 7.70; N, 7.70 0.33 found C, 66.03; H, 7.63; N, 7.68 TLC: Rf 0.44 (1:4 EtOAc:hexanes) HPLC (method retention time 12.86 min FAB MS: m/z 540 +H) I H NMR (300 MHz, CDCl3): 5 7.25-7.45 (in, 5H), 7.20 (in, 2H), 7.02 (in, 2H), 5.11 (AB quartet, 2H), 4.83 (in, IH), 3.03 3H), 2.32 (s, 3H), 1.04 3H), 0.96 3H).
EXAMPLE 77 1 -((7,7-dimethyl-2-endo-methyl(2S-amino-4-(methylsulfonyl)butanoyl)amino-bicyclo(2.2. I )heptan- 1 -yl)methanesulfonyl methvlpjhenvl D-piperazi ne To a stirred, argon purged solution of 1-((7,7-dimethyl-2endo-methyl(benzyloxycarbonyl)amino-bicyclo(2.2. I )heptan- I yl)methane-sulfonyl)-4-(2-methylphenyl)piperazine (1.1 g; 2.0 inmol) in 96:4 MeOH-HCO2H (25 mE) was added palladium black (0.4 g).
The reaction mixture was stirrred for 16 h at ambient temperature.
The catalyst was removed by filtration through Celite, and the filtrate solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 95:5:0.5 CHCI3:MeOH:NI-40H as eluant. The product, dimethyl-2-endo-methyl-amino-bicyclo(2.2. I )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazinie, was obtained as a white foam.
(0.79 g; To a stirred solution of 1-((7,7-dimethyl-2-endomethylamino-bicyclo(2.2. 1 )-heptan- I -yl)methanesulfonyl)-4-(2methylphenyl)-piperazine (0.700 g; 1.73 rnmol) in CHC13 (60 mL) was added the acid fluoride of Na-Fmoc-L-methionine sulfone (1.23 g; 3.03 WO 95/02587 PCT/US94/07769 117mmol) and DIEA (0.52 mL; 3.0 mmol). The mixture was stirred at ambient temperature for 24 h, and then extracted with 5% aqueous HCI mL), water (30 mL), and aqueous NaHCO3 (2 x 30 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was dissolved in DMF mL), and to the solution was added diethylamine (2 mL). The mixture was stirred at ambient temperature for 6 h. The solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 95:5:0.5 CHCI3:MeOH:NH40H as eluant. The title compound was obtained as a foam from CHCl3-ether (0.71 g; 61%).
Analysis: (C27H44N405S2) calc. C, 56.26; H, 7.80; N, 9.40 0.1 CHC13, 0.2 ether 1 5 found C, 56.21; H, 7.79; N, 9.22 TLC: Rf 0.10 (95:5:0.5 CHCl3:MeOH:NH40H) HPLC (method retention time 9.01 min FAB MS: m/z 569 H) 1 H NMR (300 MHz, CDC13): 8 7.18 2H), 7.03 2H), 5.20 (ddd, 1H), 3.95 (dd, 9.3, 4.1 Hz, 1H), 3.18 3H), 2.91 3H), 2.30 (s, 3H), 1.06 3H), 0.96 3H).
EXAMPLE 78 1-((7,7-Dimethyl-2-endo-methyl(2S-dimethylamino-4-(methylsulfonyl)butanoyl)amino-bicyclo(2.2.1 )heptan-1 -yl)methanesu lfonyl)-4-(2methylphenyl)-piperazine To a stirred solution of 1-((7,7-dimethyl-2-endo-methyl- (2S-amino-4-(methylsulfonyl)butanoyl)amino-bicyclo(2.2. 1)heptan-1 yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (150 mg; 0.264 mmol) in 1:1 HOAc:MeOH (6 mL) was added 37% aqueous formaldehyde (1 mL) and NaBH3CN (30 mg; 0.47 mmol). The solution was stirrred at ambient temperature for 4 h. Aqueous NaHCO3 (1 mL) was added and the solvents were removed under reduced WO 95/02587 PCT/US94/07769 -118 pressure. The residue was suspended in EtOAc (50 mL) and washed with water (2 x 25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using a wateracetonitrile gradient containing 0.1% TFA. The TFA salt of the title compound was obtained as a lyophilized powder.
Analysis: (C29H48N405S2) calc. C, 44.88; H, 5.94; N, 6.16 2.5 TFA, 1.5 found C, 44.80; H, 5.94; N, 6.18 TLC: Rf 0.45 (95:5:0.5 CHCI3:MeOH:NH40H) HPLC (method retention time 9.04 min FAB MS: m/z 597 H) 1 H NMR (400 MHz, CDC13): 8 7.2-7.3 4H), 5.15 1H), 4.79 (br t, 1H), 3.21 3H), 2.98 3H), 2.95 6H), 2.43 3H), 1.07 (s, 3H), 0.97 3H).
EXAMPLE 79 2 1 -((7,7-Dimethyl-2-endo-(4-imidazolyl)acetyl)amino-bicyclo(2.2.1)heptan-1 -yl)methanesulfonvl)-4-(2-methvl-phenyl)piperazine To a stirred so!ution of 1-((7,7-dimethyl-2-endo-aminobicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (1.50 g; 3.84 mmol) in DMF (30 mL) was added 4-imidazole acetic acid hydrochloride (0.938 g; 5.76 mmol), BOP (2.13 g; 4.80 mmol), and DIEA (2.61 mL; 15.0 mmol). The reaction mixture was stirrred for 24 h at ambient temperature, and the solvent was removed under reduced pressure. The residue was suspended in EtOAc (100 mL) and filtered through Celite to remove red polymer. The filtrate was washed with aqueous NaHCO3 (2 x 50 mL) and water (2 x 50 mL).
The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 92:8:0.8 WO 95/02587 PCT/US94/07769 -119- CHCI3:MeOH:NH40H as eluant. The title compound was obtained as white foam.
FAB MS: m/z 500 H) 1H NMR (CDC13).
EXAMPLE 1-((7,7-Dimethyl-2-endo-(2-(4-imidazolyl)propanoyl)-amino-bicyclo- (2.2.1)heptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine To a stirred solution of 1-((7,7-dimethyl-2-endo-aminobicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (1.1 g; 2.8 mmol) in DMF (25 mL) was added 2-(1acid hydrochloride (0.920 g; 3.10 mmol), BOP (1.35 g; 3.05 mmol), and DIEA (1.50 mL; 8.61 mmol). The reaction mixture was stirrred for 1 h at ambient temperature, and more DIEA (ca. 0.2 mL) was added to bring the mixture to pH 8. After another 1 h, the solvent was removed under reduced pressure. The residue was dissolved in CHC13 (150 mL) and washed with aqueous NaHCO3 (2 x 50 mL) and water (2 x 50 mL).
The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give a solid. Recrystallization from EtOAc gave crystals (0.51 g) which, by 1H NMR anlalysis, proved to be a 90:10 mixture of isomers (product The filtrate was purified by pressurized silica gel column chromatography using 95:5 CHC13:MeOH as eluant, giving a white foam (1.0 1H NMR indicated this material to be a 1:2 mixture of isomers (product Products A and B were individually deblocked by hydrogenation for 24 h at ambient temperature in 3:1 MeOH:HOAc using 25 weight palladium black under 1 atmosphere of hydrogen. The catalyst was removed by filtration through Celite and the solvents were removed under reduced pressure. Catalyst was removed by filtration through Celite, and the filtrate solvents were removed under reduced pressure. The residue derived from product A was purified by preparative reverse phase WO 95/02587 PCT/US94/07769 120- HPLC using a water-acetonitrile gradient containing 0.1% TFA. The TFA salt of the title compound (90:10 mixture by 1 H NMR) was obtained as a lyophilized powder. Product B was purified by pressurized silica gel column chromatography using 95:5:0.5 CHCI3:MeOH:NH40H as eluant. The title compound was obtained as white foam from CHCl3-ether (1:2 mixture by 1 H NMR). The two isomers had identical chromatographic behavior.
Analysis: (C27H37N503S) calc. C, 60.36; H, 7.49; N, 12.46 0.25 CHC13, 0.25 ether found C, 60.49; H, 7.26; N, 12.48 TLC: Rf 0.30 (93:7:0.7 CHCI3:MeOH:NH40H) HPLC (method retention time 8.79 min FAB MS: m/z 514 H) 1H NMR (400 MHz, CDCI3): 6 7.75 (br s, 1H), 7.20 2H), 7.0 (m, 3H), 4.40 1H), 2.30, 2.29 (two singlets, ca. 2:1 ratio, 3H), 1.57, 1.53 (two doublets, J=7 Hz, ca. 2:1 ratio, 3H), 1.00 3H), 0.96 (s, 3H).
Analysis: (C27H37N503S) caic. C, 48.91; H, 5.36; N, 9.03 2.3 TFA found C, 48.99; H, 5.21; N, 9.03 TLC: Rf 0.30 (93:7:0.7 CHC13:MeOH:NH40H) HPLC (method retention time 8.79 min FAB MS: m/z 514 H) 1 H NMR (400 MHz, CDC13): 6 8.43 1H), 7.70 1H), 7.25 (m, 2H), 7.20 1H), 7.15 2H), 4.40 1H), 4.03 J=7Hz, 1H), 2.38 3H), 1.57 J=7Hz, 3H), 1.00 3H), 0.95 3H).
WO 95/02587 PCIT/US94/07769 121 EXAMPLE 81 1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-(1 -(l-N-(methoxycarbonyl- 5ethyl)prolyl)arnino)propylbicyclo-(2.2. 1 )heptan- 1 -yl)methanesulfonyl)- S4-(2-niethyl-phenyl)piperazine
H
3 0 -0CH 3 To a stirred solution of 1 ,7-dimethyl-2-exo-hydroxy-2endo-2-( 1 -(L-prolyl)amino)propyl-(2.2. 1 )bicycloheptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (1.50 g; 2.74 mniol) in (15 ml-) was added methyl acrylate (0.3 10 mL; 3.43 mnmol).
72 h at ambient temperature, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% TFA.
The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C33H52N406S) caic. C, 53.10; H, 6.59; N, 6.82 1.65 TFA found C, 53.09; 6.58; N, 6.88 TLC: Rf 0.55 (95:5 CHCI3:MeOH) IHPLC (method retention time 9.45 min WO 95/02587 WO 9502587PCTIUS94/07769 122 FAB MS: m/z 633 (M-4 H) I H NMR (400 MHz, CDCl3): 6 7.18 (in, 2H), 7.03 (mn, 2H), 4.55 (in, 1H), 3.72 3H), 2.32 3H), 1.15 3H), 1.04 3H), 1.01 J=6 Hz, 3H).
EXAMPLE 82 1 ,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1 -(l-N-(carboxyethyl)- 10prolyl)amino)propyl-bicyclo(2.2. 1 )-heptan- 1 -yl)methanesulfonyl)-4-(2- To a stirred solution of 1 -diinethyl-2-exo-hydroxy-2endo-2 .(I1-(L-N-(methoxycarbonylethyl)-prolyl)amino)propyl- (2.2.1 )bicyclo-heptan- 1 -yl)inethanesulfonyl)-4-(2-methylphenyl)- (1.00 g; FW=82 1; 1.22 inmol) in THF (15 mEL) was added 1 M NaOH until a pH 10 solution persisted for 1 h. The solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile*water gradient containing 0. 1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
WO 95/02587 PTU9/76 PCT/US94/07769 123 Analysis: (C32H50N406S) caic. C, 51.88; H, 6.34; N, 6.80 1.8 TFA found C, 51.87; H, 6.28; N, 6.82 TLC: Rf 0.40 (80:20:2 CHC13:MeOH:NII4OH) HPLC (method retention time 8.88 min FAB MS: m/z619 +H) H NMR (400 M}Iz, CDCl3): 6 8.50 (br s, I1H), 7.20 (in, 2H), 7.05 (in, 2H), 2.33 3H), 1.12 3H), 1.03 3H), 0.99 J=6 Hz, 3H).
EXAMPLE 83 1 ,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1-(3-piperidinylcarbonyl)> amino)propyl-bicyclo(2.2.1I)heptan- 1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine
OCCH
3
N
Ns
H
HCt(OH
N
N
H H 250H To ai stirred solution of 1 -((7,7-dimethyl-2-exo-hydroxy-2endo-2-( I -amino)propyl-(2 .2.1 )bicycloheptan- I -yl)methanesulfonyl)-4- (2-methylphenyl)piperazine (2.50 g; 5.57 mmol) in DMF (35 mL) was added N-Fmoc-piperidine-3-carboxylic acid (2.15 g; 6.13 mrnol), BOP (2.75 g; 6.20mimol), and DIEA (2.16 mL; 12.4 inmiol). After 16 h, diethylamine (6 mL) was added and the solution was stirred at ambient temperature for 4 h. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc (150 mL) and washed WO 95/02587 WO 9502587PCT11JS94/07769 124with aquous NaHCO3 (2 x 75 mL) and water (2 x 75 inL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography, using 93:7:0.7 CHCl3:MeOH:NH4OH as eluant. The title compound (1:1 mixture of diastereomers) was obtained as a white foam.
Analysis: (C30H48N404S) caic. C, 56.37; H, 7.49; N, 8.54 0.8 CHC13 found C, 56.49; H, 7.44; N, 8.50 TLC: Rf 0.40 (90:10:1 CHCl3:MeOH:N-4.OH) HPLC (method retention time 8.67 min FAB MS: m/z 561 +H) I H NMR (300 MHz, CDCI3): 8 7.50 (br s, I1H), 7.20 (in, 2H), 7.02 (in, 2H), 2.30 3H), 1.17 3H), 1.00-1.04 (overlapping singlet and doublet, 6H) EXAMPLE 84 1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1 1-methoxycarbonyleth yl)pipe ri dinylIcarbon yl) -amin o)propylI-bi cycl o(2.2. 1 )heptan- I xi 'wnethanesulfonfl-4-(2-methvlp~henyl)p2iperazine
H
NS.. 0 OCH 3 WO 95/02587 WO~~~c 95057/TUS94/07769 .125 To a stirred solution of 1-((7,7.-dimethyl-2-exo-hydroxy-2endo-2-( 1-(3 -piperidinylcarbonyl)-amino)propyl-(2.2. I )bicycloheptan- 1 -yl)methansulfonyl)-4-(2-methylphenyl)piperazine (0.50 g; 0.89 mrnol) in methanol (10 mL) was added methyl acrylate (0.110 m-L; 1.34 mmol). After 72 h at ambient temperature, the solvent was -emo Jd under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% TFA. The TFA salt of title compound 1 mixture of diastereomers) was obtained as a lyophilized powder.
Analysis: (C34H54N406S) caic. C, 55.40; H, 7.06; N, 7.08 1.25 TFA, 0.1 found C, 55.39; H, 7.05; N, 7.03 TLC: Rf 0.35 (95:5 CHCl3:MeOH) HPLC (method retention time 10.71 min FAB MS:mnxz 647 +H) I H NMR (400 MHz, CDCl3): 8 7.20 (in, 2H), 7.02 (in, 2H), 3,72, 3,69 (two singlets, 3H), 2.32, 2.31 (two singlets, 3H), 1.16, 1.15 (two singlets, 3H), 0.98-1.04 (two coincident singlets and two overlapping doublets, 6H).
EXAMPLE 1 ,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1 -carboxyethyl)piperidinylcarbonyl)amino)-propylbicyclo(2 .2.1 )heptan- I -yl)methanesulfonyvl)-4-(2-methylphenyl)piperazine WO 95/02587 PCT/US94/07769 126-
CH
3
N
,-S
SO2 H3C OH 0 H H N
OH
0 To a stirred solution of l-((7,7-dimethyl-2-exo-hydroxy-2endo-2-(1-(3-(1-methoxycarbonyl)piperi-dinylcarbonyl)amino)propyl(2.2.1 )-bicycloheptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.30 g; 0.46 mmol) in THF (10 nmL) was added 1 M NaOH until a pH 10 solution persisted for 1 h. The solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt of title compound (1:1 mixture of diastereomers) was obtained as a lyophilized powder.
Analysis: (C33H52N406S.
calc. C, 51.59; H, 6.44; N, 6.54 1.9 TFA, 0.4 found C, 51.60; H, 6.44; N, 6.83 TLC: Rf 0.15 (80:20:2 CHCI3:MeOH:NH40H) HPLC (method retention time 10.27 min FAB MS: m/z 633 H) 0 H NMR (400 MHz, CDC13): 5 7.20 2H), 7.05 2H), 2.39, 2.32 (two singlets, 3H), 1.12, 1.11 (two singlets, 3H), 0.95-1.03 (two coincident singlets and two overlapping doublets, 6H).
WO 95/02587 PTU9/76 PCT/US94/07769 127 EXAMPLE 86 1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1 -ethoxycarbonylmethyl)piperi dinylIcar-bony1) amino)p ropylI-bi cyclIo 1 )heptan- 1 yl)methanesulfonvl)-4-(2-methvlphenvl)piperazine
CH
3
N
N, CO 2 Et
N
*OHN
H 3 C H To a stirred solution of 1-((7,7-dimethiyl-2-exo-hydroxy-2endo-2-( 1-(3 -piperidinylcarbonylI)amino)-p ropyl1-(2.2. 1 )bicycloheptan- 1 -yl)methaniesulfonyl)-4-(2-methyl-pheinyl)piperazine (0.50 g; 0.89 mmol) in DMF (5 mL) was added ethyl bromoacetate (0.110 mL; 0.99 mmol) and DIEA (0.172 mL; 0.99 mmol). After 24 h at ambient temperature, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 m.L) and washed with 5% aqueous citric acid (25 mL), water (25 mL), and aqueous NaHCO3 (25 mL).
The organic phase was dried (MgSO4), filtered, and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel columrn chromatography, using 1:1 EtOAc:C-C13 as eluant. The title compound 1 mixture of diastereomers) was obtained as a white foam.
Analysis: (C34H54N406S) calc. C, 58.66; H, 7.77; N, 7.93 0.5 CHC13 found C, 58.87; H, 7.83; N, 7.88 TLC: Rf 0.28 (1:1 CHC13:EtOAc) WO 95/02587 WO 9502587PCTF/US94/07769 128 HPLC (method retention time 9.76 min FAB MS: m/z 647 +H) I H NMR (300 MHz, CDCI3): 5 8.2 (very br s, 1H), 7.18 (in, 2H), 7.03 (mn, 2H), 4.20 (two very closely spaced quartets, 2H), 2.30, 2.31 (two singlets, 3H), 1.28 J=7 Hz, 3H), 1.07, 1.08 (two singlets, 3H), 1.03- 1.08 (two coincident singlets and two overlapping doublets, 6H) EXAM7PLE 87 1 -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1 -carboxymethyl)piperidinylcarbonyl)amnino)-propylbicyclo(2.2. 1 )heptan- I -yl)methanesu Ifonvi )-4-(2-methvlphenvl)p2iperazine
CH
3
N
Nso KC02H
N
Hy
.ON
H.
3
H
To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2endo-2-( I -methoxycarbonyl)-pi pe ridin ylIcarbonylI)amino)propyl (2.2.1 )bicycloheptan- 1 -yl)methanesulfonyl )-4-(2-methylphenyl)piperazine (0.360 g; 0.555 rmol) in THF (5 mL) was added I M NaOH until a pH 10 solution persisted for I h. The solution was made acidic by the addition of HOAc (1 m.L) and evaporated under reduced pressure. The residue was suspended in CI-2C12 and filtered. The filtrate was evaporated under reduced pressure several times from CH2CI2 to give the title compound 1 mixture of diastereoiners) as a white foam.
WO 95/02587 WO 95/2587 CIUS94O7 769 129 Analysis: (C32H50N406S) caic. C, 58.27; H, 7.62; N, 7.99 1.0 NaOAc found C, 58.47; H, 7.71; N, 7.90 TLC: Rf 0.55 (85:15 CHCl3:MeOH) HPLC (method retention time 8.77 min FAB MS: m/z 619 +H)
I
1 H NMR (300 MHz, CD3OD): 857.15 (in, 2H), 7.05 J=7.3 Hz, I1H), 6.96 J=7.3 Hz, 1H), 2.31 3H), 1.17 1.03 3H), 0.98 (d, J=6 Hz, 3H).
EXAMPLE 88 1 ,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1 -(l-N-(ethoxycarboxymethyl)-prolyl)amino)propyl-bicyclo-(2.2. 1 )heptan- 1 1).methanes ulfonyl)-4-(2-methv1~henvj)pip erazine
OH
3
NS
OHN
0 3 H N 0 0
-CH
2
CH
3 0 3 To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2endo-2-( I-(L-pr-olyl)aminio)propyl(2.2. 1)-bicycloheptan-1I-yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (0.20 g; 0.37 mmol) in DMF rnL) was added ethyl bromoacetate (0.045 m.L; 0.40 immol) and DIEA (0.071 mL; 0.41 rnmol). After 24 h at ambient temperature, the solvent was removed under reduced pressure and the residue was WO 95/02587 WO 9502587PCIT/US94/07769 130purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C33H52N406S) caic. C, 54.25; H, 6.79; N, 7.07 1.4 TFA found C, 54,25; H, 6.78; N, 7.02 TLC: Rf 0.50 (1:1 EtOAc:CHCl3) HPLC (method retention time 9.68 min MS: m/z 633 +H) I H NMR (400 MHz, CD3OD): 8 7.17 (in, 2H), 7.06 1=6Hz, I1H), 6.98 J=6Hz, I1H), 4.25 (mn, 3H), 4.08 J= 15 Hz, I 3H), 1.27 J=7 Hz, 3H), 1.18 3H), 1.03 3H), 1.01 1=6 Hz, 3H).
EXAMPLE 89 1 ,7-Diinethyl-2-exo-hydroxy-2-endo-2-( 1 -(l-N-(carboxymethyl)prolyl)amino)propyl-bicyclo(2.2. I )-heptan- I -yl)methanesulfonyl)-4-(2methilihen Mlerazine H3 OHN Y
N
H
3 C" H
H
OH
To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2endo-2-( 1 -ethoxycarbonylImethyl])-pro Iy l)ami no)propy I- WO 95/02587 WO 9502587PCT/US94/07769 131 (2.2.1 )bicycloheptan- I -yl)methane-sulfonyl)-4-(2-m-ethylphenyl)piperazine (0.20 g; 0.32 mmoi) in THF (5 mE) was added 1 M NaOuntil a pH 10 solution persisted for 1 h. The solven~t was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Alialysis: (C3 1 H48N406S) calc. C, 52.64; H, 6.43; N, 7.22 1.5 TFA found C, 52.49; H, 6.51; N, 7.22 TLC: Rf 0.40 (80:20:2 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.79 min FAB MS: m/z 605 +H) 1 H NMR (400 MHz, CD3OD): 8 7.17 (in, 2H), 7.07 (d J=5 Hz, 1H), 6.99 J=5 Hz, 1LH), 4.30 (dd, J=4, 5 Hz, 1 4.21 J= 14 Hz, I H), 4.04 J=14 Hz, 1H), 2.32 3H), 1.18 3H), 1.03 3H), 1.01 (d, J=7 Hiz, 3H).
EXAMPLE 1 -((7,7-Dimethyl-2-exo-hyciroxy-2-endo-2-( 1-(4-piperidinylcarbonyl)amino)propyl-bicyclo(2.2. 1 )heptan- I -yl)methanesulfonyl)-4-(2-methiylphenvl'piperazineoC H 3
N,
H
3
C
WO 95/02587 WO 95/2587 PCT!LUS94/0 769 132- To a stirred solution of 1-((7,7-dirnethyl(', -o-hydroxy-2endo-2-(l1-amino)propyl-(2 .2.1 )bicycloheptan- 1-yI)metL .,.esulfonyl)-4- (2-methylphenyl)piperazine (1.50 g; 3.34 mmol) in DMF (20 mL) was added N-Fmoc-piperidiine-4-carboxylic acid (1.29 g; 3.67 mmol), BOP (1.64 g; 3.70 mmol), and DLEA (1.28 mL; 7.34 mmol). After 16 h, diethylamnine (5 mL) was added and the solution was stirred at ambient temperature for 4 h. The solvents were removed under reducedpressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile -water gradient containing 0. 1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C30H48N404S) calc. C, 51.93; H, 6.43; N, 7.15 1.95 TFA, 0.05 found C, 51.93; H, 6.36; N, 7.28 Rf 0.15 (90:10:1 CHCl3:MeOH:NH4OH) HPLC (method retention time 8.33 min FAB MS: m/z561 +H) I H NMR (400 MI-z, CDC]I3): 5 7.20 (in, 3H), 7.08 (mn, 2.33 (s, 3H), 1. 14 3H), 1.02 3H), 1.00 J=6 Hz, 3H).
EXAMPLE 91 1 ,7-Diinethyi -2-exo-hydroxy-2-endo-2-( 1 -inethoxycarbonylethyl)-piperidinylcarbonyl)-amino)propyl-bicyclo(2.2. 1 )heptan- I1vl)iethiane-sulfonyl)-4-(2-methyl-p2henvl)piperazifle WO 95/02587 PCT/US94/07769 133
CH
3 SO2 0 H3C" H 0
OHN
To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2endo-2-(1 -(4-piperidinylcarbonyl)amino)-propyl-(2.2.1 )bicycloheptan- 1-yl)methane-sulfonyl)-4-(2-methylphenyl)piperazine (0.30 g; 0.53 mmol) in methanol (5 mL) was added methyl acrylate (0.072 mL; 0.80 mmol). After 48 h at ambient temperature, the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C34H54N406S) calc. C, 53.04; H, 6.65; N, 6.60 1.75 TFA, 0.15 found C, 53.05; H, 6.62; N, 6.69 TLC: Rf 0.25 (95:5 CHCl3:MeOH) HPLC (method retention time 9.02 min FAB MS: m/z 647 H) 1 H NMR (400 MHz, CDC13): 6 7.45 (br t, 1H), 7.21 2H), 7.09 (m, 2H), 3.72 3H), 2.33 3H), 1.15 3H), 1.00-1.02 (overlapping s and d, 6H).
WO 95/02587 WO 9502587PCTIUS94/07769 134 EXAMPLE 92 1 -((7,7-Dirnethyl-2-exo-hydroxy-2-endo-2-( 1 -carboxyethyl)piperidinylcarbonyl)amino)propyl-bicyclo-(2.2. 1 )heptan- Il-yI )methanesulfonyl)-4-(2-methvlp~henvl)p2iperazine Oo H 3 ,N
OH
OHN
150 To a stirred solution of 1 ,7-dimethyl-2-exo-hydroxy-2endo-!-( 1 -methoxycarbonyl)pipe-ridinylcarbonyl)amino)propyl (2.2.1 )bicycloheptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.15 g; 0.23 mmol) in
T
HF (5 mL) was added I M NaOH until a pH 10 solution persisted for 1 h. The solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containaing 0. 1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C33H52N406S) calc. C, 53.09; H, 6.65; N, 6.84 1.6 TFA, 0.2 found C, 53.08; H, 6.66; N, 6.85 TLC: Rf 0.10 (80:20:2 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.72 min FAB MS: mlz 633 +H) WO 95/02587 WO 9502587PCT/US94/07769 135 iH NMR (400 MHz, CDCI13): 857.3 8 (br s, I1H), 7.18 (in, 2H), 7.03 (mn, 2H), 2.29 3H), 1.13 3H), 0.98-1.01 (overlapping s and d, 6H).
EXAMPLE 93 I -((7,7-Dimethyl-2-exo-hydroxy-2-endo-2-( 1-(3 -ethoxycarboriylmethyl)piperidinylcar-bonyl)amino)propyl-bicyclo(2.2. 1 )heptan- 1 vi )methanesulfonyl)-4-(2-methylphenyl)p2iperazine
H
N.-
S02 OH N 0
CH
2
CH
3 0 To a stirred solution of 1-((7,7-dimethyl-2-exo-hydroxy-2endo-2-(1 -(3-piperidinylcarbonyl)amino)-propyl-(2.2. 1 )bicycloheptan- 1 -yl)methanesulfonyl)-4-(2-methylplienyl)piperazine (0.20 g; 0.36 inmol) in DMF (5 m.L) was added ethyl bromoacetate (0.044 mL; 0.40 mmol) and DIEA (0.070 m.L; 0.40 mmol). After 24 h at ambient the solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
Analysis: (C34H54N406S) caic. C, 52.81; H, 6.67; N, 6.57 1.75 TFA, 0.35 found C, 52.80; H, 6.64; N, 6.69 TLC: Rf 0.35 (95:5 CI-C13:MeOH) HPLC (method retention time 9.26 min WO 95102587 WO 9502587PCT/US94/07769 136 FAB MS: m/z 647 +H) I H NMR (400 MHz, CDC13): 8 7.19 (in, 2H), 7.04 (in, 2H), 4.26 (q, J=7 Hz, 3.85 2H), 2.32 3H), 1.29 J=7 Hz, 3H), 1.14 (s, 3H), 1.02-1.05 (overlapping s and d, 6H).
EXAMPLE 94 1 ,7-Diinethyl-2-exo-hydroxy-2-endo-2-( 1 -carboxymethyl)piperidinylcarbonyl)amino)propyl-bicyclo(2.2. 1 )heptan- I -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine a 7
CH
3
N
NS
OHN
N~OH
3
O
0 To a stirred solution of 1-((7,7-diinethyl-2-exo-hydroxy-2endo-2-(1 -methoxycarbonylmethyl)-piperidinylcarbonyl)aino)- 25propyl-(2.2. 1 )bicycloheptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.15 g; 0.23 inmol) in THF (5 mL) was added 1 M NaOH until a pH 10 solution persisted for 1 h. The solution was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% TFA. The TFA salt of title compound was obtained as a lyophilized powder.
WO 95102587 WO 95/2587 CT/US94/07769 137 Analysis: (C32H50N406S) caic. C, 53.23; H, 6.82; N, 7.18 1.3 TFA, 0.75 found C, 53.20; H, 6.8 1; N, 7.18 TLC: Rf 0.15 (80:20:2 CHC13:MeOH;NlI-40H) HPLC (method retention time 8.59 min FAB MS: m/z 619 +H) I H NMR (400 MHz, CDCI3): 8 7.35 (br s, 1H), 7.17 (in, 2H), 7.02 (in, 2H), 3.90 2H), 2.30 2H), 1.13 3H), 1.01 3H), 0.97 J=6 Hz, 3H).
EXAMPLE 1 ,7 -DimethylI-2-endo -(2S -diethyl amino (methylI-sulIfonyl)butyr- 15amido)-bicyclo(2.2. 1 )herptan- 1 -yl)methanesulfonyl)-4-(2-methylpheny I1i ~erazine
CH
3
N
HNN
Ol S0 2 0H 3
H
3 C CH 3 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfoniyl)butyramido)-bicyclo(2.2. 1 )-heptan- Il-yl)methanesulfonyl)-4-(2-methylphenyl)-piperazie (100 mg; 0.18 mmol) in methanol containing I acetic acid (2 mL) was added acetaldehyde (0.033 rnL; 0.6 mmol) and sodium cyanoborohydride (10 mg; 0.18 -n, WO 95/02587 PCT/US94/07769 138 mmol). After 2 h, the reaction was quenched with sodium bicarbonate solution (0.5 mL) and the solvent was removed under reduced pressure.
The residue was taken up in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (2 x 25 mL), brine (2 x 25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 95:5:0.5 CHCl3:CH30H:NH40H.
The title compound was obtained as a white foam by evaporation under reduced pressure from ether-chloroform in 85% yield.
Analysis: C30H50N405S2, 0.7 CHC13, 0.2 (CH3CH2)20 calc. C, 53.65; H, 7.51; N, 8.01 found C, 53.64; H, 7.50; N, 8.13 TLC: Rf 0.38 (95:5:0.5 CHC13:MeOH:NH40H) HPLC (method retention time 9.66 min, purity FAB MS: m/z 611 (M H+) EXAMPLE 96 1 -((7,7-Dimethyl-2-endo-(2S-ethoxycarbonylmethyl-amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-1 -yl)methanesulfonyl)-4- (2-methylphenyl)-piperazine
CH
3 N.so2 H N H O CH 3 LC 11~1_1_ 1 WO 95/02587 PCT/US94/07769 139 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. I1)-heptan-1yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (200 mg; 0.36 mmol) in DMF (3 mL) was added DIEA (0.070 mL; 0.40 mmol) and ethyl bromoacetate (0.044 mL; 0.40 mmol). After 24 h, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and washed with 5 wt% aqueous citric acid (2 x 25 mL) and saturated sodium bicarbonate solution (2 x 25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 95:5 CHCl3:CH30H. The title compound was obtained as a white foam by evaporation under reduced pressuic' from EtOAc-hexane in 75% yield.
Analysis: C30H48N407S2, 0.4 EtOAc, 0.05 hexane calc. C, 56.30; H, 7.69; N, 8.23 found C, 56.22; H, 7.70; N, 8.25 TLC: Rf 0.35 (95:5 CHCl3:MeOH) HPLC (method retention time 9.67 min, purity 99+% FAB MS: m/z 641 (M H+) EXAMPLE 97 1-((7,7-Dimethyl-2-endo-(2S-carboxymethylamino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1)heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenvl)piperazine WO 95/02587 PCT/US94/07769 140- S .CH 3
N
o SO2 2 HN"
H
O OH To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Sethoxycarbonyl-methylamino-4-(methyl-sulfonyl)butyramido)bicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (50 mg; 0.08 mmol) in ethanol, was added 1 N aqueous sodium hydroxide to obtain a pH 13 reaction solution. After 24 h, the reaction was acidified to pH 2 with 5% aqueous HCI and the solvent was removed under reduced pressure. The residue was taken up in methylene chloride (25 mL), washed with brine (25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was triturated in ether and filtered to give the title compound as a white solid in 75% yield.
Analysis: C28H44N407S2. 0.5 NaCI calc. C, 52.38; H, 6.91; N, 8.73 found C, 52.43; H, 6.55; N, 8.80 TLC: Rf 0.2 (90:10:0.2:0.2 CHCI3:MeOH:H20:HOAc) HPLC (method retention time 8.91 min, purity 99% FABMS:m/z 613(M H+) WO 95/02587 iPcT1uS94/07769 141 EXAMPLE 98 I ,7-Dimethyl-2-endo-(2S-ar-nino-4-(methylsulfoniyl)-butyramido).
bicyclo(2.2. 1 )heptan- I -yI)rnethanesulIfony1) -4-(2-methyl1-5 -flu orophenvl)-piperazine ja H3
FN
NS
HN
H
0SO 2
CH
3
NH
2 The title compound was prepared from 1 ,7-dimethyl-2endo-amino-bicyclo(2.2. 1 )heptan- 1 -yl)methane-sulfonyl)-4-(2-methyl- 5-fluoro-phenyl)piperazine and Boc-L-methioritne sulfone using the procedures set forth in Examples 71 and 72. The crude product was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to &give a white powder in 85% yield.
Analysis: C26H4lFN405S2, .3H20, 1.7 CF3COOH caic. C, 45.74; H, 5.65; N, 7.26 found C, 45.74; H, 5.65; N, 7.50 TLC: Rf 0.18 (95:5:0.5 CHCI3:MeOH:N4O0H) HPLC (method retention time =8.86 min, purity 99% FAB MS: m/z 573 (M H+) 0~r 95/02587 PCT/US94/07769 142 EXAMPLE 99 1 ,7-Dimethyl-2-endo-(2S -dimethylamino-4-(methyl-su ifonyl )butyramido)-bicyclo(2.2. 1)heptan-1I-yl)methanesulfonyl)-4-(2-methyl-5fluorophenyl)piperazine "C H3
FN
N..
H N%
H
0J- S2H
H
3 C O H 3 The title compound was prepared from 1-((7,7-dimethyl-2- 20endo-(2S-arnino-4-(methylsulfonyl)-butyramido)-bicyclo(2.2. I )heptan- 1 -yl)methanesulfonyl)-4-(2-methyl -5 -fluorophenyl)piperazine using the procedure set forth in Example 74. The crude product was purified by preparative reverse phase HPLC using an acetonitrile-water gradient 0. 1% trifluoroacetic acid. The trifluoroacetate salt of the compound was obtained by lyophilization to give a white powder in yield.
Analysis: C28H45FN405S2, 0.05 1H20, 1.65 CF3COOHcaic. C, 47.59; H, 5.97; N, 7.09 found C, 47.56 5.9 1;N, 7.15 TLC: Rf 0.39 (95:5:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 9.82 mini, purity 99% FAB MS: m/z 601 (M H+) WO 95/02587 WO 9502587PCT/US94/07769 143 EXAMPLE 100 I -((7,7-Dimethyl-2-endo-(2S-( I -piperidinyl)-4-(methylsulfonyl)butyramido)-bicyclo(2 .2.1 )heptan- I -yl )methanes ulfonyl methvlp~henv]lpiperazine QC H 3 N 0 HN
H
0 SO 2
CH
3 0 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyrarnido)-bi cyclo(2.2. 1 )-heptan- I ylmethianesulfonyl)-4-(2-methyl-phieny l)piperazine (100 mg; 0.18 mmol) in methanol containing 1 by volume of acetic acid in methanol mL) was added glutaraldehyde (25 wt% in water; 0.005 mL;, 0.22 mmol) and sodium cyanoboro-hydride (30 mg; 0.54 mmol). After 3 h, the reaction was quenched with aqueous sodium bicarbonate solution rnL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (25 m.L) and washed with saturated aqueous sodium bicarbonate (2 x 25 mL), brine (2 x 25 rnL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The title compound was obtained as a white foam in yield.
WO 95/02587 WO 9502587PCT/US94/07769 144 Analysis: C3 IH50N405S2, 0.85 caic. C, 58.33; H, 8.17; N, 8.78 found C, 58.3 1; 7.77; N, 8.67 TLC: Rf 0.45 (95:5:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.72 min, purity 99+% FAB MS: m/z 623 (M H+) EXAMPLE 101] 1 ,7-Dimethyl-2-enido-(2S-(2-hydroxyethyl)amino-4-(methiylsulfonyl)-butyramido)-bicyclo(2.2. 1)heptan- 1-yl)methanesulfonyl)-4- (2-methyl -phenyl )pJiperazine
OH
3 HN H S0 2 0H 3 A stirred solution of I -((7,7-dimethyl-2-endo-(2S-amnino-4- (methylsulfony'l)butyramido)-bicyclo(2.2. I )-heptan- I -yl)methanesulfonyl)-4-(2-methylphenyl)piperaziine (310 mg, 0.56 mmol) in ethanol mL) was cooled to 0 0 C. Ethylene oxide was bubbled through the solution, the reaction vessel was sealed, and the reaction mixture was warmed to 70'C. After 48 h, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography using a gradient elution of 97:3 to 93:7 CHCI3:MeOHto separate the faster running bis-alkylated product from the miono- WO 95/02387 WO 9502387PCT/1JS94/07769 145 alkylation product. The title compound was obtained as a white foam by evaporation under reduced pressure from CHCI3-MeOH in yield.
Analysis: C28H46N406S2, 0.4 CHCI3, 0.15 MeOH, calc. C, 52.64; H, 7.27; N, 8.60 found C, 52.67; H, 7.27; N, 8.37 TLC: Rf 0. 15 (93:7 CHCI3:MeOH) HPLC (method retention time 8.72 mini, purity 99% FAB MS: mlz= 599 (M EXAMPLE 102 1 ,7-Dimethyl-2-endo-(2S-(4-morpholinyl)-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- 1 -ylI)m ethane sulfon y1) (2-methyl p2henvl)pip~erazine rI H
N..
0 l- SO 2
CH
3
C:)
To a solution of 1-((7,7-dimethyl-2-endo-(2S-amino-4- (m-ethylsulfonyl)butyramido)-bicyclo(2.2. I )heptan- I -yl)methanesulfonyl)-4-(2-metlhylphenyl)piperazine (100 mg, 0.18 mmol) in DMF (3 mL) was added bis(2-chloroethyl)-ether (0.029 m.L; 0.25 mnmol), WO 95/02587 PCT/US94/07769 146sodium iodide (75 mg; 0.5 mmol), and sodium carbonate (80 mg; 0.75 mmol). The mixture was flushed with argon and heated at 130 0 C for 6 h. The solvent was removed under reduced pressure. The residue was suspended in ethyl acetate (50 mL) and washed with water (2 x 25 mL), saturated aqueous sodium bicarbonate (2 x 25 mL), brine (25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in yield.
Analysis: C30H48N406S2, 3.0 CF3CO2H, 0.5 calc. C, 44.31; H, 5.37; N, 5.74 found C, 44.20; H, 5.04; N, 6.10 1 5 TLC: Rf 0.63 (95:5:0.5 CHCl3:MeOH:NH40H) HPLC (method retention time 9.08 min, purity 100% FAB MS: m/z 625 (M H+) EXAMPLE 103 1-((7,7-Dimethyl-2-endo-(2S-cyanomethylamino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazie -I rrR_~.
WO 95/62587 PCTIUS94/07769 147 CH 3
N
N'SO
HN
O
SO
2
CH
3
HN
HN
C =N To a solution of 1-((7,7-dimethyl-2-endo-(2S-amino-4- (methylsulfonyl)butyramido)-bicyclo(2.2.1 I)heptan- I -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg, 0.18 mmol) in chloroform (5 mL) was add-u fEA (0.037 mL; 0.21 mmol) followed by iodoacetonitrile (0.015 mL; 0.21 mnol). After 24 h, the reaction was diluted with chloroform (50 miL) and washed with water (25 mL), saturated aqueous sodium bicarbonate (2 x 25 mL), brine (25 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography using 97:3 dichloromethane:methanol as eluant. The title compound was obtained as a white foam in 70% yield.
Analysis: C28H4 3N5O5S2, 0.5 calc. C, 55.79; H, 7.36; N, 11.67 found C, 56.15; H, 7.42; N, 11.32 TLC: Rf 0.45 (95:5:0.5 CHCI3:MeOH:NH40H) HPLC (method retention time 9.78 min, purity 100% FAB MS: m/z 594 (M H+) WO 95/02587 PTU9/76 PCTIUS94/07769 148 EXAMPLE PA 1 ,7-Dimethyl-2-endo-(2S-(4-tetra-hydropyranyl)amino-4-(methylsulfonyl)-butyramido)-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4- (2-methyl- phenvi )pDierazine
~CH
3
N
N~s HN'
H
S0 2 0H 3 HN 0 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino (methylIsulIfon yl)butyrami do) -bi cyclIo I )-heptan-1 yl)methanesuilfonyl)-4-(2-methylphenyl )-piperazine (200 mg; 0.36 mmol) in methanul containing 1I% by volume of acetic acid (4 mL) was added 4-5 molecular sieves (34) tetrahydropyran-4-one (0.037 mL, 0.37 mmol) and sodium cyanoborohydride (20 mg; 0.36 mmnol). After 2 h, the reaction was quenched with aqueous sodium bicarbonate mL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2 x 50 mL), brine (2 x 50 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The title comnpound was obtained in 90% yield as a white foam.
WO 95/02587 WO 9502587PCT/US94/07769 149 Analysis: C3 1H-50N4002, 0.45 EtOAc, caic. C, 58.05; H, 7.96; N, 8.26 found C, 57.8 1; H, 7.7 1; N, 8.28 TLC: Rf 0.27 (95:5:0.5 CHCI3:MeOH:NI-40H) HPLC (method retention time 8.29 min, purity 99% FAB MS: m/z =639 (M EXAMPLE 105 1 -((7,7-Dimethyl-2-endo-(2S-(2-aminoethyl)amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. I )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)p2iperazine
OH
3 N~s HN H OJI
SO
2
CH
3 To a stirred solution of l-((7,7-dimethyl-2-endo-(2Samino (methylIsulIfonylI)butyrami do)bi cyclIo I )-heptan- 1 yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg; 0.36 mmol) in methanol containing I by volume of acetic acid (4 ml-) was 4-5 molecular sieves N-Boc-glycinal (62 mg, 0.39 mmol) and sodium cyanoboro-hydride (20 mg; 0.36 mmol). After 2 h, the reaction was quenched with aqueous sodium bicarbonate (0.5 mL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (50 ml-) and washed with saturated aqueous sodium bicarbor-ite (2 x 50 mL), brine (2 x 50 mL), dried over _I WO 95/02587 PCT/US94/07769 150magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography using 95:5 chloroform:methanol as eluant to give 1- ((7,7-dimethyl-2-endo-(2S-(2-(tert-butyloxycarbonylamino)ethyl)amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1)heptan-lyl)methanesulfonyl) 4-(2-methylphenyl)piperazine in 80% yield. This compound was dissolved in methylene chloride (7 mL) and to the solution was added trifluoroacetic acid (7 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in methylene chloride (70 mL) and washed with saturated aqueous sodium bicarbonate (3 x 100 mL), brine (2 x 50 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The title compound was lyophilized from dioxanewater to give a white powder in 90% yield.
Analysis: C28H47N505S2, 0.5 C4H802, 1.5 calc. C, 53.87; H, 8.14; N, 10.47 found C, 54.04; H, 8.96; N, 10.44 TLC: Rf 0.08 (90:10:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 9.30 min, purity 99% FAB MS: m/z 598 (M H+) WO 95/02587 PTU9/76 PCT/US94/07769 151 EXAMPLE 106 1 -((7,7-irniethy1-2-endo-(2R-amino-4-(methylsulfonyl)-butyramido>bicyclo(2.2. 1)heptan- 1-yl)methanesu lforiyl )-4-(2-methyiphenyl)pip erazine
~CH
3
N
HN
H
0J SO 2
CH
3
H
2
N
1 ,7-Dimethyl-2-endo-(2R-(tert-bu tyloxy-carbonyl amnino-4-(methylthio)bu tyramido)-bicyclo(2.2. 1 )-heptan- I -yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine was prepared from Boc-Dmethionine and 1- ,7 -dimethyl-2 -endo -amino -bic yclIo 1)heptan- 1yl)methanesulfonyl)-4-(2-methylphenyl)piperazine using the procedure set forth in Example 35. 1 ,7-Diniethyl-2-endo-(2R-(tert-butyloxycarbonyl)amino-4-(methylthio)butyramido)-bicyclo(2.2. 1 )heptan- 1 yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg; 0.32 mmol) was dissolved in 3:1 MeOH:water (25 mL) and to the solution was added sodium acetate (200 mng; 2.6 mmol) and Oxone® (0.80 g; 1.3 mmol). After 24 h, the solvents were removed under reduced pressure and the residue was purified by silica gel flash column chromatography using 90: 10:1 CHCI3:MeOH:NH-40H as eluant to give 1-((7,7-dimethyl- 2-endo-(2R-(tert-butyloxycarbonyl)amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- I -yl)methanesu Ifonyl )-4-(2-methyl phenyl)piperazine-4-N -oxide as a foam from chloroform in 70% yield.
This product was dissolved in THF (3 mL) and treated with WO 95/02587 PCT/US94/07769 152 triphenylphosphine (79 mg; 0.35 mmol). After 24 h the solvent was removed under reduced pressure and the residue was purified by silica gel flash colunm chromatography using 1:1 EtOAc:hexane as eluant to give 1 -((7,7-dimethyl-2-endo-(2R-(tert-butyloxycarbonyl)-amino-4- (methylsulfonyl)butyramido)-bicyclo(2.2. )heptan- -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine as a white foam in 90% yield.
This product was dissolved in dichloromethane (5 mL) and treated with TFA (4 mL). After 1 h, the solvents were removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (4 x 25 mL), brine (25 mL), dried (MgSO4), filtered, and the solvents were removed under reduced pressure. The residue was purified by silica gel flash column chromatography using a gradient elution of 98:2:0.2 to 95:5:0.5 CHCl3:MeOH:NH40H. The title compound was obtained as a white foam by evaporation under reduced pressure from ether in 90% yield.
Analysis: C26H42N5405S2, 0.9 H20, 0.3 ether calc. C, 55.07; H, 7.95; N, 9.44 found C, 55.08; H, 7.57; N, 9.17 TLC: Rf 0.33 (94:6:0.5 CHCI3:MeOH:NH40H) HPLC (method retention time 8.85 min, purity 99% FAB MS: m/z 555 (M H+) EXAMPLE 107 1-((7,7-Dimethyl-2-endo-(4-(methylsulfonyl)butyramido)-bicyclo- (2.2.1)-heptan- I -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine WO 95/02587 PCT/US94/07769 -153
N
SO2 02 HN H ojSO 2
CH
3 To a stirred solution of 4-(methylsulfonyl)-butyric acid (370 mg; 2.23 mmol), in DMF (25 mL) was added BOP (986 mg; 2.23 mmol), 1-((7,7-dimethyl-2-endo-amino-bicyclo(-2.2.1)heptan-1yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (960 mg; 2.45 mmol), and DIEA (7.84 mL; 4.5 mmol). After 16 h, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL). The organic solution was washed with 5 wt% aqueous citric acid (2 x 50 mL), saturated aqueous sodium bicarbonate (3 x 50 mL), and brine. The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by flash silica gel column chromatography using 1:1 ethyl acetate:hexane as eluant. The title compound was obtained as a white foam in 90% yield.
Analysis: C26H41N305S2,0.25 C2H5CO2CH3,0.25 calc. C, 57.26; H, 7.74; N, 7.42 found C, 57.26; H, 7.54; N, 7.32 TLC: Rf 0.18 (1:1 EtOAc:Hexane) HPLC (method retention time 10.62 min, purity 99.7% FAB MS: m/z 548 (M H+) WO 95/02587 PCT/US94/07769 154 EXAMPLE 108 1-((7,7-Dimethyl-2-endo-(2S-bis(hydroxyethyl)amino-4-(methylsulfonyl)-butyramido)-bicyclo(2.2. I )heptan- l-yl )methanesulfonyl)-4- (2-methyl-phenyl)piperazine
CH
3
N
Ns HN H OS0 2
CH
3 HO N OH A stirred solution of 1-((7,7-dimethyl-2-endo-(2S-amino-4- (methylsulfonyl)butyramnido)-bicyclo(2.2. 1 )-heptan- I -yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (310 mg, 0.56 mmol) in ethanol (10 mL) was cooled to 0 0 C. Ethylene oxide was bubbled through the solution, the reaction vessel was sealed, and the reaction mixture was warmed to 70 0 C. After 48 h, the reaction was cooled to 0 0 C and ethylene oxide was bubbled through the solution. The reaction vessel was sealed and heated at 70 0 C for 48 h. The solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in yield.
Analysis: C30H50N407S2, 2.2 CF3CO2H, 0.35 calc. C, 45.90; HI, 5.92; N, 6.23 found C, 45.90; H, 5.89; N, 6.33 WO 95/02587 PCT[US94/07769 155 TLC: Rf 0.62 (90:10:0.5 CHC13:MeOH:N1-40H) HPLC (method retention time 8.93 min, purity 98+% FAB MS: m/z= 643 (M EXAMPLE 109 1 ,7-Dimethyl-2-endo-(2S -(4-tetrahydrothi;opyranyl )-amnino-4- (methylsulfonyl)butyramido)-bicyclo-(2.2. 1 )heptan- 1. -yl)methanesu Ifonyi)-4-(2-methVlphenvl)p2iperazine
N
NS02 HN
H
SO
2
CH
3 HN
S
The title compound was prepared from 4-tetra-hydrothiopyranone and 1 ,7-dimethyl-2-endo-(2S-arnino-4-(methlylsu ifonyl)butyramido)-bicyclo-(2.2. I )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine using the procedure set forth in Example 104. The crude product was purified by silica gel flash chromatography eluting with 97:3:0.3 CHCI3:CH3OH:NI-40H. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform in 95% yield.
WO 95/02587 WO 95/2587 CTIUS94/07769 156 Analysis: C31IH50N40'S3, 0.75 CHCI3 caic. C, 51.22; 6.87; N, 7.53 found C, 51.29; H, 6.83; N, 7.27 TLC: Rf 0.44 (95:5:0.5 CHCI3:MeOH:NB4OH) HPLC (method retention time 9.91 min, purity 99% FAB MS: m/z =655 (M EXAMPLE I -((7,7I-Dimethyl-2-endo-(2S-(, 1, -dioxo-4-tetrahydrothio-pyranyl)am-ino-4-(methylsulfonyl)butyramido)-bicyclo-(2.2. 1 )heptan- 1 vl)methanesulfonyl)-4-(2-methvlphenvl )-pip~erazine So 2 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2S-(4tetrahydrothiopyranyl)amino-4-(methy isulfonyl )-butyramido)bicyclo(2.2. I )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (90 mg, 0.12 mmol) in 1:9 H20:acetone (3 mL) was added 4-methylmorpholine-N -oxide (43 mg, 0.36 mmol) and 0s04 (0.013 mL of 2.4 wt% solution). After 17 h the reaction was quenched with saturated aqueous NaHSO3 (0.05 mL), and the solvent was removed under reduced pressure. The residue was taken up in methylene WO 95102587 WO 9502587PCI/US94/07769 157 chloride (25 mL) and washed with IN NaHSO3 (3 x 25 mL), brine (2 x dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 0. 1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in yield.
QCI1H50N407S3, 2.05 CF3CO2H, 0.35 calc. C, 45.47; H, 5.74; N, 6.04 found C, 45.47; H, 5.72; N, 5.89 TLC: Rf 0.33 (95:5:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 9.02 min, purity 99% MS: mlz= 687 (M EXAMPLE 111 1 ,7 -Dimeth yl -2 -end o-(2S -acetamido-4-(meth yl -sulfonylI)butyr- 20amido)-bicyclo(2.2.1I)heptan-1I-yl)methane-sulfonyl)-4-(2-methyl- 2henyl)piperazine crc C13
N
S024s
SO
2
CH
3 WO 95/02587 WO 9502587PCTIUS94O 7769 158 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1)-heptan- 1yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (160 mg, 0.29 mmnol) in chloroform (5 mL) was added acetic anhydride (1 mL), and dilsopropylethylamine (0.03 mL). After 2 h the solvent was removed under reduced pressure. The residue was dissolved in chloroform mL) and washed with 5% aqueous HCI (2 x 10 mL), water (10 mL), saturated aqueous sodium bicarbonate (2 x 10 mL), brine (10 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure to give the title compound as a foam in yield.
Analysis: C28H44N406S2, 0.5 CHCI3, calc. C, 55.89; H, 7.37; N, 9.30 found C, 55.90; H, 7.36; N, 9.22 TLC: Rf 0.21 (95:5:0.5 CHCI3:MeOH:NI-40H) HPLC (method retention time 9.01 min, purity 99% FAB MS: mlz= 597 (M EXAMPLE 112 I -((7,7-Dimethyl-2-endo-(2S-(2-cyanoethyl)amino-4-(methylsulfonyl)butyrarnido)-bicyclo(2.2. I )heptan- 1 -yl)metlianesulfonyl)-4-(2-methylphnyl)p2iperazine WO 95/02587 WO 9502587PCI'/US94/07769 159 C. H 3 N N-
HNN
o S0 2 0H 3 HN C N To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino (methylIsulfonyl)butyrani do) -bi cycl o(2.2. 1 )-heptan-I 1 yl )methanesuitfonyl)-4-(2-methylpl ,enyl )piperazine (200 mg, 0.36 mmol) in MeGH was added acrylonitrile (0.026 mL, 0.40 mmol). After 16 h, an additional amount of acrylonitrile (0.010 mEL, 0.15 mmol) was added. After 24 h the solvent was removed under reduced pressure.
The residue was purified by silica gel flash column chromatography using 1:3 EtO. ic:hexanes as eluant. The s )lvent was removed under redhiced pressure and the residue was triturated in EtOAc and hexanes.
The solid was dried in vacuo for 16 h to give the title compound as a white powder in 55% yield.
Analysis: C29H45N505S2, 0.32 EtOAc calc. C, 57.18; H, 7.54; N, 11.01 found C, 56.86; H, 7.74; N, 11.01 TLC: Rf 0.2 (1:4 EtOAc:hexanes) HPLC (method retention time 8.99 min, purity 99% 3 0 FAB MS: m/z= 608 (M WO 95/02587 PTU9/76 160 EXAMPLE 113 1 -Dimethyl-2-endo-(2S -(2-hydroxy-2,2-dimethyl-ethy1)amino-4- (methylsulfonyl)butyramido)-bicyclo(2.2. 1 )-heptan- I -yl)methanesulfonvv)-4-(2-methylphenylpDiperazine C H 3
N
SO
2
HN"
H N ',SO 2
CH
3 CH3
OH
To a stirred solution of 1-((7,7-dimnethyl-2-endo-(2Samino (methylIsulfonyl)butyrami do) -bi cyclIo 1 )-heptan- 1 yl)methanes ulfonyl) (2-methylphenyI ])pipe razine (200 mg, 0.36 mmol) in EtOH (5 mL) was added isobutylene oxide (0.026 mL, 0.36 mmol) and the reaction was sealed and heated on a steam bath. After 16 h, an additional amnount of isobutylene oxide (0.026 mL, 0.36 mmol) was added and heating was continued. After 24 h, an additional amount of isobutylene oxide (0.026 ml-, 0.36 mmol) was added and heating was continued. After 24 hi the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to 'ield a white powder in 48% yield.
WO 95/02587 PI'crus94/o7769 161 Analysis: C30H50N406S2,l1.7 CF3CO2H, 0.4 caic. C, 48.45; H, 6.39; N, 6.77 found C, 48.46; H, 6.37; N, 6.78 TLC: Rf 0.3 (95:5:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.56 min, purity 97% FAB MS: m/z= 627 (M H+) EXAMPLE 114 1 -Dimethyl-2-endo-(2S-(2-R-hydroxypropyl)amino-4(methyl.
sulfonyl)-butyramido)-bicyclo(2.2. I )heptan- I -yl)methanesulfonyl)-4- (2-methvlphenvl)piperazine
CH
3
ON
SS2 HN H
SO
2
CH
3
H
3 0 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1 )-heptan- -1yl)methanesulfonyl)-4-(2-methylphenyl )piperazine (200 mg, 0.36 mmol) in EtOH (5 mL) was adcP.d R-(+)-propylene oxide (0.025 mL, 0.36 mmnol) and the reaction was sealed and heated on a steam bath.
After 16 h, an additional amount of R-(+)-propylene oxide (0.010 mL, 0.15 mmol) was added and heating was continued. After 72 h the solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using an acetonitrile-water WO 95/02587 WO 9502587PCTIUS94/07769 162 gradient containing 1I% trifluoroacetic acid. The faster running of two products was isolated and lyophilized to give the trifluoroacetate salt of the title compound as a white powder in 42% yield.
Analysis: C29H48N406S2, 1.75 CF3CO2H, 0.5 caic. C, 47.52; H, 6.23; N, 6.82 found C, 47.50; H, 6.22; N, 6.90 TLC: Rf 0.2 (95:5:0.5 CHC13:MeOH:N1-40H) HPLC (method retention time 8.34 min, purity 99% FAB MS: m/z= 613
H+)
EXAMPLE 115 1 ,7-Dimethyl-2-endo-(2S-bis(2R-hydroxypropyl)amino-4.,(methylsulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- I -yl)methanesulfonyl)-4- (2-methvlphenyl )piperazine C H 3 200
NN
HO, OH 3
L
The slower running of two products isolated from the preparative HPLC purification of the crude product from Example 78 WO 95/02587 WO 9502587PcT/US94/07769 163 was lyophulized to give the trifluoroacetate salt of the title compound as a white powder in 2% yield.
Analysis: C32H54N407S2, 1.9 CF3CO2H, 0.15 caic. C, 48.49; H, 6.36; N, 6.29 found C, 48.31; H, 6.35; N, 6.52 TLC: Rf 0.2 (95:5:0.5 CHCl3:MeOH:NH4OH) HPLC (method retention time 8.74 min, purity FAB MS: m/z= 671 (M EXAMPLE 116 1 ,7-Dimethyl-2-endo-(2S-(2S-'Lydroxypropyl)amino-4-(methylsulfonyl)butyramnido)-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4- LZ-methylphenvl~piperazine
~.CH
3
N
NS0 HN
H
oj S0 2 0H 3 HN 0H
H
3 0 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino (methylIsulfonyl)butyrami do) )-bi cycl o(2.2. I )-heptan- 1 yl)methanesulfonyl)-4-(2-methylpheflyl)piperazine (200 mg, 0.36 rrol) in EtOH (5 mL) was added S-(-)-propylene oxide (0.025 mL, 0.T E'mmol) and the reaction was sealed and heated or, a steam bath.
After 16 h, an additional amount of S-(-)-propylene oxide (0.010 mL, 0. 15 mmol) was added and heating was continued. After 72 h the WO 95/02587 PCTIUS94/07769 164solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1% trifluoroacetic acid. The faster running of two products was isolated and lyophilized to give the trifluoroacetate salt of the title compound as a white powder in 24% yield.
Analysis: C29H48N406S2, 1.8 CF3CO2H, 0.3 calc. C, 47.54; H, 6.17; N, 6.80 found C, 47.55; H, 6.16; N, 6.90 13 TLC: Rf= 0.2 (95:5:0.5 CHCI3:MeOH:NH40H) HPLC (method retention time 8.40 min, purity 99% FAB MS: m/z= 613 (M H+) EXAMPLE 117 1-((7,7-Dimethyl-2-endo-(2S-bis(2S-hydroxypropyl)amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1)heptan- -yl)methanesulfonyl)-4- (2-methylphenyl)piperazine
CH
3 N s s 2
H
HN
O v SO 2
CH
3
OH
OH 'CH 3
CH
3 The slower running of two products isolated from the preparative HPLC purification of the crude product from Example 116 WO 95/02587 WO 95/2587 CT/US94/07769 165 was lyophilized to give the trifluoroacetate salt of the title compound as a white powder in 5% yield.
Analysis: C32H54N407S2, 1.9 CF3CO2H, 0. 15 caic. C, 48.37; H, 6.41; N, 6.32 found C, 48.36; H, 6.42; N, 6.52 TLC: Rf 0.2 (95:5:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.78 min, purity 97% FAB MS: m/z= 671 (M H+) EXAMPLE 118 1 ,7-Dimethyl-2-endo-(2S -(2-propyl)amino-4-(methyl-sulfonl.
butyramido)-bicyclo(2.2. 1)heptan- 1-yl)methane-sulfonyl)-4-(2methylp~henvi )iperazine Oc H 3
QN
HNN
H0 S0 2 0H O H 3
OH
3 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1)-heptan- 1yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in EtOH (5 mL) was added acetone (0.026 mE, 0.40 mrnol) and activated, crushed 3A sieves. After 5 h, NaBH3CN (11I mg, 0.36 mmol) was added. After 16 h an additional amount of NaBH3CN (5 mg, 0.15 WO 95/02587 'I'CT/US94/07769 166mmol) was added. After 24 h one drop of water was added and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile-water gradient containing 1% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization to give a white powder in yield.
Analysis: C29H48N405S2, 1.7 CF3CO2H, 0.8 calc. C, 48.33; H, 6.42; N, 6.96 found C, 48.33; H, 6.42; N, 7.14 TLC: Rf 0.6 (95:5:0.5 CHCl3:MeOH:NH40H) HPLC (method retention time 9.68 min, purity 99% FAB MS: m/z= 597 (M H+) EXAMPLE 119 1-((7,7-Dimethyl-2-endo-(2S-(4-pyridyl)amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine Cx CH 3
N
WO 95/02587 WO 9502587PCTIJS9d/07769 167 To a stirred solution of l-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1I)-heptan- 1yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in DMF (10 mL) was added 4-bromo-pyri dine (70 mg, 0.36 3 mrnol) and the reaction was heated to 120'C for 16 h. Much degradation occurred. The solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acet onitri le -water gradient containing 1I% trifluoroacetic acid.
The triflu oro -acetate salt of the title compound wa-s obtained by lyophilization to give a white powder in 2.5% yield.
Analysis: C31IH45N405S2, 2.05 CF3CO2H, 1.35 caic. C, 47.37; H, 5.63; N, 7.87 found C, 47.36; H, 5.93; N, 7.48 TLC: Rf 0.4 (95:5:0.5 CHCl3:MeOH:NH4OH) HPLC (method retention time 9.23 min, purity 93% FAB MS: m/z= 632 (M H+) EXAMPLE 120 1 -Dimethy 1 2-endo-(2S-(2-fluoroethyl)amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- I -yl )methanesulfonyl)-4-(2-methylphenyl)piperazine
OH
3
XN
30S0 OJII. S0 2 0H 3 H N
F
WO 95/02587 WO 95/2587 CTJUS94/07769 168 To a stirred solution of 1-((7,7-dimethyl-2-endo-(2S- P 'ilo-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1)-heptan-1 thanesulfonyl)-4-(2-methylphenyl)piperazine (200 mg, 0.36 mmol) in DMF (5 mE) was added 1,2-bromo-fluoroethane (0.025 mL, 0.36 mmol) and the reaction was sealed and heated on a steam bath.
After 16 h the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using an acetonitrile -water gradient containing 1I% trifluoroacetic acid. The trifluoroacetate salt of the title compound was obtained by lyophilization give a white powder in 18% yield.
Analysis: C28FH45N405S2, 1.8 CF3CO2H caic. C, 47.08; H, 5.85; N, 6.95 found C, 47.09; H, 5.86; N, 7.04 TLC: Rf 0.4 (95:5 CHC13:MeOH) HPLC (method retention time 8.50 min, purity 99% FAB MS: m/z= 601 (M H+) EXAMPLE 121 1 ,7-D imethyl -2-endo-(QS -ethyl amino-4- (methy I- sulIfonylI)butyramido)-bicyclo(2.2. 1 )heptan- 1 -yl)methane-sulfonyl)-4-(2-methylphenay 1) pip erazine
OH
3 30S2 HN
H
SO
2
CH
3
HN"-CH
3 WO 95/02587 PCT/US94/07769 169- To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Samino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )-heptan-lyl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.206 g; 0.371 mmol) in DMF (30 mL) was added iodoethane (0.015 mL; 0.19 mmol) followed by DIEA (0.097 mL, 0.56 mmol). The reaction was stirred at ambient temperature for 48 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (3 x 50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with 98:2:0.2 CH2Cl2:MeOH:NH40H. The resulting oil was dissolved in CH3CN and H20 containing 0.1% TFA and lyophylized to give the trifluoroacetate salt of the title compound as a white powder in 40% yield.
Analysis: C28H46N405S2 0.15 H20, 0.85 TFA FW 682.451 calc. C, 52.57; H, 6.96; N, 8.21 found C, 52.30; H, 6.92; N, 8.19 TLC: Rf 0.46 (96:4:0.4 CH2C12:MeOH:NH40H) HPLC (method retention time 8.43 min, 99% purity FAB MS: m/z 583 (M H+) WO 95/02587 PCT/US94/07769 170- EXAMPLE 122 1-((7,7-Dimethyl-2-endo-(2S-(tert-butyloxycarbonyl)-methylamino-4- (methylsulfonyl)butyramido)-bicyclo-(2.2. I)heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine
CH
3
N
N,
S02 HN
H
OSO 2
CH
3
NH
H
3
C
A solution of N-Boc-N-methyl-L-methionine sulfone (0.899 g; 3.04 mmol) and BOP (1.35 g, 3.00 mmol) in DMF (50 mL) was stined for 10 min. A solution of 1-((7,7-dimethyl-2-endo-aminobicyclo(2.2. 1)heptan-1 -yl)methane-sulfonyl)-4-(2-methylphenyl)piperazine (1.80 g; 2.77 mmol) in DMF (15 mL) was added dropwise to the reaction followed by DIEA (5.2 mL; 3.0 mmol) to bring the reaction mixture to pH 8 (as judged by spotting an aliquot on wetted E.
Merck pH paper). After 16 h the DMF was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL) and washed with 5 wt% aqueous citric acid (100mL) and saturated aqueous sodium bicarbonate (2 x 100 mL). The organic layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 40:60 hexane:EtOAc. The title compound was obtained as a white foam in 90% yield.
WO 95/02587 WO 9502587PCT[US94/07769 171 Analysis: C32H52N407S2 0.25 EtOAc FW 690.95 caic. C, 57.36; H, 7.88; N, 8.11 found C, 57.68; H, 7.84; N, 8.13 TLC: Rf 0.27 (40:60 hexane:EtOAc) HPLC (method retention time 11.21 min, 99-t purity FAB MS: mlz 669 (M H+) EXAMPLE 123 1 ,7-Dimethyl-2-endo-(2S-methyla-mino-4-(methyl -sulfonyl )butyramido)-bicyclo(2.2. 1 )heptan- 1 -yl)methane-sulfonyl)-4-(2-rnethylp2henyl')pip~erazine
OH
3 S0 2 HN H
SO
2
CH
3 N H
H
3
C
To a stirred solution of 1 -((7,7-dimethyl-2-enido-(2S-(tertbutyloxycarbonyl)methylamino-4-(methylsulf-onyl)butyramido)bicyclo(2.2. I )heptan- 1 -yI)methane-sulfonyl)-4-(2-methylphenyl)piperazine (1.0 g; 1.5 mmol) in DCM (25 mL) was added TFA mL). The reaction was stirred at ambient temperature for 1 h. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc (100 mL) and washed with saturated aqueous sodium bicarbonate (4 x 50 mL). The organic layer was dried WO 95/02587 PTU9/76 PCT/US94/07769 172 (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as a foam in 95% yield.
Analysis: C27H44N405S2 0.40 EtOAc 0.45 H20 FW 612.15 calc. C, 56.11; H, 7.92; N, 9.15 found C, 56.14; H, 7.78; N, 9.16 TLC: Rf 0. 16 (97:3 DCM:MeOH) HPLC (method retention time 8.23 min, 99+% purity FAB MS: mlz =569 (M EXAMPLE 124 1 ,7-Dimethyl-2-endo-(2S-trideateromethylamino-4-(methiyl- 15sulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4- 15(2-methylp~henyl)p2iperazine
,CH
3 N, S0 2 D3
C--N
The title compound was prepared from N-Boc-N--trideuteromethyl-L-methionine su Ifone and 1 -dimethyl-2-endo-aminobicyclo(2.2. 1 )heptan- 1 -yl)methiane-sulfonyl)-4-(2-methylphenyl)piperazine using the procedures set forth in Examples 122 and 123.
The title compound was obtained as a white foam by evaporation under reduced pressure from EtOAc-hexane.
WO 95/02587 WO 95/2587 C'r1US94/07769 173 Analysis: C27D3H4lN405S2 0.35 EtOAc, 0.20 H20 FW 606.22 caic. C, 56.26; H, 7.28; N, 9.24 found C, 55.93; H, 7.67; N, 9.18 TLC: Rf 0.16 (97:3 DCM:MeOH) HPLC (method retention time 8.23 min, 99+% purity FAB ML): m/z =572 EXAMPLE 125 1 -((7,7-Dmty -no(Sbstieueoehlaio4(ehl sulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4- (2-methylp~henyl 'piperazine-
CH
3 HN H S0 2 0H 3 030- CD 3 A stirred solution of 1 -dimethyl-2-endo-(2S -amino-4- (methylsulfonyl)bu-,yramido)-bicyclo(2.
2 1 )-heptan- I -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (0.433g, 0.781 mmol) and (0.203 mL; 1.17 rmmol) in DMF (10 mL) was cooled to 0 0
C.
lndomethane-d3 (0.50 mL, 0.786 mmol) was added dropwise via syringe. The reaction was gradually warmed to ambient temperature and then stirred for 16 h. The reaction was cooled to 0 0 C and an additional 0.5 eq of CD31 and DLEA were added, and the reaction was stirred for 16 h. at ambient temperature. The solvent was removed WO 95/02587 IPCT/US94/07769 174under reduced pressure and the residue was dissloved in EtOAc mL). The EtOAc solution was washed with saturated aqueous sodium bicarbonate (2 x 25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure. HPLC analysis of the crude product S indicated the presence of unreacted mono-, bis-, and tris-alkylated products. The desired bis-alkylated product was isolated by silica gel flash column chromatography eluting with 98:2 CH2Cl2:MeOH. Pure fractions were combined and the solvent was removed under reduced pressure to give an oil. The oil was lyophilized from 1:2 CH13N:H20 containing 0.1% TFA to give the trifluoroacetate salt of the title compound as a white powder.
Analysis: C28D6H40N405S2 0.80 TFA, 2.45 H20 FW 724.256 calc. C, 49.08; H, 6.36; N, 7.74 found C, 49.12; H, 6.55; N, 7.43 TLC: Rf 0.43 (95:5:0.5 HPLC (method retention time 8.33 min, 99+% purity FAB MS: m/z 589 (M H+) EXAMPLE 126 1-((7,7-Dimethyl-2-endo-(2S-tris(trideuteromethyl)amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan-1 -yl)methanesulfonyl)-4- (2-methylphenyl)piperazine trifluoroacetate WO 95/02587 WO 9502587PCT/US94/07769 175
CH
3
N
N..
HN
H
S0 2
CH
3
D
3 0 CDD3 A stirred solution of 1 -dim,,ethyl-2-endo-(2S-amino-4- 15(methylsulfonyl)butyramido)-bicyclo(2.2, 1 )-heptan- 1 -yl)methane- 15sulfonyl)-4-(2-methylphenyl)piperazine (0.426 g, 0.768 mmol) and DIBA (0.40 mL; 2.3 mm-ol) in DMF (20 mE) was cooled to 0 0
C.
Iodomethane-d3 (0.16 mE; 2.5 mmol) was added dropwise via syringe.
The reaction was gradually warmned to ambient temperature and stirred 48 h. The solvent was removed under reduced pressure and the resie _;was purified by preparative reverse-phase HPLC using a wat-r:acetonitrile gradient contamng 0. 1% TFA. The title compound was obtained by lyophilization to give a white powder in 50% yield.
Analysis: C31IH4D9F30N407S2 0.6 TFA FW 788.284 calc. C, 49.06; H, 6.34; N, 7.11 found C, 49.13; H, 6.61; N, 6.96 TLC: Rf 0.11 (90:10:0.5 DCM:MeOH:NH4OH) HPLC (method retention time 8.51 min 99+% purity FAB MS: m/z 606 WO 95/02587 WO 95/2587 C'r/US94/07769 176 EXAMPLE 127 1 -Dimethyl-2-endo-(2S-N ,N-dimethylformamidinyl-4-(methy1 sulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- I -yl)methanesulfonyl)-4- (2-methylp~henyl)p2iperazine
CH
3 N~s HN
H
0SO 2
CH
3
N
0 -H3 Y
CH
3
H
To a stirred solution of l-((7,7-dimethyl-2-endo-(2Samino (methylIsulIfonyl)butyrami do) -bi cy clIo(2.2. 1 )-heptan- 1yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg; 0.18 rnmol) in DMF (2 mL) was added dimethyl-formamide-dimethylacetal (xx mL; 0.54 mmol). After 24 h, the solvent was removed under reduced pressure. The resulting oil was diassolved in EtOAc (50 mL) and washed with water (2 x 25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform in 90% yield.
Analysis: C29H47N505S2 0.4 CHCI3, calc. C, 53.70; H, 7.27; N, 10.65 found C, 53.87; H, 7.27; N, 10.66 WO 95/02587 WO 9502587PCTIUS94107769 177 TLC: Rf 0.35 (95:5:0.5 HPLC (method retention time 8.34 min, 99+% purity FAB MS: mlz=610(M EXAMPLE 128 1 ,7-Dimethyl-2-endo-(2S-acetamidinyl-4-(methyl-sulfonyl)butyramido)-bicyclo(2.2.1I)heptan- 1-yl)me thane-sulfonyl)-4-(2-methylphenvl)p2iperazine 0a
CH
3
N
S0 2 UJM H
SO
2
CH
3
NH
2
Y
CH
3 To a stirred solution of 1 -((7,7-dimethyl-2-endo-(2S- -4 -(methylIsulfonyl)butyrami do) -bi cycl o(2.2. 1 )-heptan- 1..
yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (100 mg; 0.18 mmol) in DMF (4 mL) was added methyl acetimidate hydrochloride (100 mg; 0.91 mmol) and sodium carbonate (150 mg; 1.5 mmnol). After 3048 h, the mixture was filtered through Celite and the solvent was removed under reduced pressure. The resulting dark oil was purified by silica gel flash column chromatography using a gradient elution of 95:5:0.5 CHCI3:MeOH:NI-40H to 85:15:0.75 CHCI3:MeOH:N1-40H.
The trifluoroacetate salt of the title compound was obtained as a white WO 95/02587 WO 9502587PCI'/US9d/07769 178 powder in 25% yield by lyophilization from 1:3 CH3CN:H20 conta-ining 0. 1% TFA.
Analysis: C28H45N505S2 1.0 TFA, 1.5 caic. C, 49.90; H, 6.70; N, 9.50 found C, 48.7 1; 6.45; N, 9.62 TLC: Rf 0.29 (85:15:0.75 CHC13:MeOH:NII4OH) HPLC (method retention time 9.05 min, 97.9% purity FAB MS: m/z 596 (M EXAMPLE 129 1 ,7-Dimethyl-2-endo-(2S-(4-(I1 -tert-butyloxycarbony)-piperidinyl)- 15amino-4-(methylsulfonyl)butyramido)-bicyclo-(2.
2 1 )heptan- 1vi )methaniesulfonvl)-4-(2-methVlphenvl )-piperazine C H 3 H N
H
0 S0 2 0H 3 H N N0 OH 3 0 C HH To a stirred solution of 1-((7,7-dimethyl-2-endo-(2Sam~ino -4-(methy Isulforyl)butyrami do)-bi cyclo( 2 2 I )-heptan- 1 yl)methanesulfonyl)-4-(2-methylpheflyl)piperazine (200 mg; 0.36 i WO 95/02587 PCT/US94/07*69 179mmol) in methanol containing 1% by volume of acetic acid (4 mL) was added 4-5 molecular sieves 1-tert-butyloxycarbonyl-4piperidinone (78 mg, 0.39 mmol) and sodium cyanoborohydride mg; 0.36 mmol). After 5 h, the reaction was quenched with aqueous sodium bicarbonate (0.5 mL) and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2 x 50 mL), brine (2 x 50 mL), dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel flash coumn chromatography using 95:5 CHCl3:MeOH as eluant. The resulting oil was lyophilized from H20:CH3CN containing 0.1% TFA. The trifluoroacetate salt of the title compound was obtained in 85% yield as a white powder.
Analysis: C36H59N507S2, 0.45 H20, 2.5 TFA calc. C, 47.75; H, 6.10; N, 6.79 found C, 47.76; H, 6.07; N, 7.12 TLC: Rf 0.27 (95:5 CHCl3:MeOH) HPLC (method retention time 10.72 min, purity 99+% FAB MS: m/z 738 (M H+) EXAMPLE 130 1-((7,7-Dimethyl-2-endo-(2S-(4-piperidinyl)amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2. 1)heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine WO 95/02587 WO 95/2587 CT/US94/07769 180 C.
CH
3
N
HNN
oj
SO
2
CH
3 H N
NO
To a stirred solution of 1-((7,7-dimethyl-2-endo-(2S-(4-(1tert-butylIoxycarbon y)piperidinyl) amino (methylIsulfonylI)butyramido)-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine 10 g; 0. 14 mmol) in dichloromethane (20 mL) was added TFA (15 mL). After 1 h, the solvents were removed under reduced pressure and the residue was, dissolved in EtOAc (50 ml-) and washed with saturated aqueous sodium bicarbonate (4 x 25 mL), brine mL), dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel flash colun chromatography using 90: 10:1 CHCl3:MeOH:NH4OH as eluant. The title compound was obtained as a white foam in 90% yield by evaporation under reduced pressure from diChloromethane.
Analysis: C3 I H5 1 N505S2, 0.6 CH2Cl2 calc. C, 55.13; H, 7.70; N, 9.79 found C, 55.09; H, 7.64; N, 10.07 TLC: Rf 0.11 (90: 10:1 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.13 min, purity 99+% FAB MS: m/z =638 H+) WO 95/02587 WO 9502587PCT/US94/07769 181 EXAMPLE 131 1 ,7 -Dimethyl -2-Endo-(2S -Amin r,-4 -Hydroxybutyramido)bicyclo (2.2.1 )Heptan- 1 -vl')Methanesulfonyl)-4-(2-Methylphenvl)p2iperazine
OH
3
HN
OH
H
2
N
To a stirred solution of -dimethyl1-2-endo -aminobicyclo(2.2. I )heptan- 1 -yl)methanesulfonyl)-4-(2-rnethylphenyl)piperazine (2.0 g; 5.1 mmol) in DMF (20 mL) was added N-Boc-Lhomoserine, O-benzyl ether (1.73 g; 5.61 mrnol), hydroxybenzotriazole hydrate (0.87 g; 5.7 mmol), DIBA (2.0 rnL; 1 1.5 mmol), and EDC (1.09 g; 5.7 mmol). After 24 h, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL) and washed with 5% aqueous citric acid (2 x 25 mL), water (25 mL), saturated aqueous sodium bicarbonate (2 x 50 mL), dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel flash column chromatography using 1:1 ethyl acetate:hexane as eluant. 1 ,7-Dimethyl-2-endo-(2S-tertbutyloxycarbonylarnino-4-(benzyloxy)butyramido)-bicyclo(2.2. 1)heptan- I -yl)methanesulfonyl)-4-(2-methiylphenyl)piperazinie was obtained as a white foam in 90% yield. This compound was Ndeprotected by dissolving in dichloromethane (15 mL) and adding TFA mL). After I h, the solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL) and washed with WO 95/02587 PC'T/US94/07769 182saturated aqueous sodium bicarbonate (4 x 50 mL), dried (MgSO4), and filtered. The solvent was removed under reduced pressure to give ((7,7-dimethyl-2-endo-(2S-amino-4-(benzyloxy)butyramido)-bicyclo- (2.2.1)heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine as a white foam in 95% yield. This compound was O-deprotected by dissolving in methanol containing 5% by volume of acetic acid (50 mL) and stirring with palladium black (150 mg) under an atmosphere of hydrogen (ambient pressure). After 24 h, the reaction was flushed with argon, the catalyst was removed by filtration through Celite, and the 0solvents were renoved under reduced pressure. The residue was purified by silica gel flash column chromatography using 90:10:1 CHCl3:MeOH:NH40H as eluant. The title compound was obtained as a white foam in 90% yield after evaporation under reduced pressure from chloroform-ether.
Analysis: C25H40N404S, 0.15 CHC13, 0.15 ether calc. C, 59.28; H, 8.05; N, 10.74 found C, 59.42; H, 8.02; N, 10.72 TLC: Rf 0.18 (90:10:1 CHCl3:MeOH:NH40H) HPLC (method retention time 8.31 min, purity 99+% FAB MS: m/z 493 (M H+) EXAMPLE 132 1-((7,7-Dimethyl-2-endo-(2s-(4-piperidinyl)amino-4-hydroxybutyramido)-bicyclo(2.2.1 )heptan-1 -yl)methanesu!fonyl 4-(2-methylphenyl)piperazine WO 95/02587 PCT/US94/07769 183
CH
3 HN N OH
H
The title compound was prepared by reductive alkylation of 1-((7,7-dimethyl-2-endo-(2S-amino-4-hydroxybutyramido)-bicyclo- (2.2.1)heptan-1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine with 1-tert-butyloxycarbonyl-4-piperidinone followed by TFA Ndeprotection using procedures analogous to those set forth in Example 93 and Example 94. The crude product was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1% by volume of TFA. The trifluoroacetate of the title compound was obtained as a white lyophilized powder in 50% yield.
Analysis: C30H49N504S, 3.9 TFA, 1.15 calc. C, 43.60; H, 5.34; N, 6.73 found C, 43.61; H, 4.95; N, 7.12 TLC: Rf= 0.10 (90:10:1 CHCi3:MeOH:NH40H) HPLC (method retention time 7.85 min, purity 99+% FAB MS: m/z 576 (M H+) WO 95/02587 WO 9502587I CT'/US94/07769 184- EXAMPLE 133 1. -DimethylI-2-endo -(2s -(4-tetrahyd ropy rany1) -amino -4-hydroxybutyramido)-bicyclo(2.2. I )heptan- 1 -yl)m-ethanesulfonyl)-4-(2-methylhenvl')piperazine 0~ N' OH
H
The title compound was prepared by reductive alkylation of 1 -dimethyl -2-endo-(2S -amino-4-hydroxybutyramido)-bicyclo- 20(2.2.1 )heptan- 1-yl)methianesulfonyl )-4-(2-rnethylphenyl )piperazine with 4-tetrahydropyranone using a procedure analogous that set forth in Example 68. The crude product was purified by silica gel flash column chromatography using 95:5:0.5 chloroform:methanol:N1140H as eluant.
The title compound was obtained as a white foam by evaporation under pressure from chlIoroform -methanol.
Analysis: C30H48N405S, 0.2 CI-C13, 0.3 calc. C, 60.02; 8. 16; N, 9.18 found C, 60.04; H, 8.09; N, 9.14 TLC: Rf 0.35 (95:5:0.5 CHC13:MeOH:N1-40H) HPLC (method retention time 8.82 min, purity 96% FAB MS: mlz= 577 (M WO 95/02587 WO 95/2587 CIT/LS94/07769 185 EXAMPLE 134 1 -((7,7-dimethyl-2-endo-(2s-(, 1, -dioxo-4-tetrahydrothiopyranyl)amino- 4-hydroxybutyramido)-bicyclo(2.2. I )heptan- 1 -yl)methanesulfonyl)-4- (2-methylphenyl)piperazine
CH
3 q
,O
HN, 0 The title compound was prepared by reductive alkylation of 1 ,7 -dimethylI-2-endo-(2S -amino -4 -hydrox ybutyrami do) -bi cyc 1o 20(2.2. 1 )hep tan 1 -y1)methanesulIfon yl)-4 -(2-methy lphen yl)p~lperazinie with 4-tetrahydrothiopyranone followed by oxidation to the sulfone using procedures analogous those set forth in Example 73 and Example 74.
The crude product was purified by silica gel flash colurnm chromatography using 95:5:0.5 chiloroform:methanol: NH4OH as eluant.
title compound was obtained as a white foam by evaporation under reduced pressure from chloroform.
Analysis: C30H48N406S2, 0.4 CHC13, 0.1 calc. C, 54.13; H, 7.26; N, 8.31 found C, 54.15; H, 6.91; N, 8.15 TLC: Rf 0.30 (95:5:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.79 min, purity 97% FAB MS: m/z 625 (M H+) WO 95/02587 WO 9502587PCI/US94/07769 186 EXAMPLE 135 1 -((7,7-dimethylI-2-endo -(2S -amino -3 -hydro xypropi onamido)bi cyclIo- (2.2.1 )heptan-1I-vI')methanesulfonyl)-4-(2-methylphenyl)p2iperazine-
CH
3 NH 0
H
2
OH
The title compound was prepared from 1-((7,7-dimethyl-2endo -amino -bicyclIo 1 )heptan- I -yl)methanesulfonyl )-4-(2-methylphenyl)piperazine and Boc-L-serine followed by TFA N-deprotection using procedures analogous to those set forth in Example 35 and Example 36. The crude product was purified by silica gel flash column chromatography using 95 :5 :0.5 CHCI3:MeOH:M-140H as eluant. The title compound was obtained as a white foam in 90% yield after evaporation under reduced pressure from ch', -oform.
Analysis: C24H38N404S, 0.35 CHC13 calc. C, 56.19; H, 7.43; N, 10.77 found C, 56.24; H, 7.50; N, 10.86 TLC: Rf 0.32 (95:5:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.23 min, purity 99+% FAB MS: mlz= 479 H+) WO 95/02587 PTU9/76 PCIVUS94/07769 187 EXAMPLE 136 1 ,7 -dimethyl -2-endo- (2S (4 -piperi diny1) amino -3 -hydroxypropionamido)-bicyclo(2.2.1I)heptan-1I-yl)methanesulfonyl)-4-(2methylp~henvl)piperazine
OH
3 00 O
N~-
H NT 0 HN 0,OH The title compound was prepared by reductive alkylation of 1 ,7-dimethyl-2-endo-(2S-amino-3 -hydroxypropiona-iido)-bicyclo- 20(2.2.1 )heptan- 1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine with 1-tert-butyloxycarbonyl-4-piperidinone followed by TFA Ndeprotection using procedures analogous to those sc~t forth in Example 93 and Example 94. The crude product was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1 volume of TFA. The trifluoroacetate of the title compound was obtained as a white lyophilized powder in 80% yield.
Analysis: C29H47N504S, 4 TFA, 0.9 CH3CN calc. C, 44.20; H, 5.14; N, 7.89 found C, 44.63; H, 4.62; N, 7.88 TLC: Rf 0.05 (90: 10:1 CHCI3:MeOH:NH4OH) HPLC (method retention time 7.99 min, purity 99+% FAB MS: m/z =562 (M WO 95/02587 WO 9502587PCT/US94/07769 188 EXAMPLE 137 1 -dimethyl-2-endo-(2S-(4-tetrahydropyranyl)arnino-3 -hydroxypropionainido)-bicyclo(2.2. 1 )heptan- I -yl)methanesulfonyl)-4-(2methvlphenyl)p2iperaz ine
OH
3
S
H N 0 0 N ,OH O -H The title compound was prepared by reductive alkylation of 1 ,7-dimethyl-2-endo-(28-aminio-3 -hydroxypropionamido)-bicyclo- 20(2.2.1 )heptan-1I-yl)methanesulfonyl)-4-(2-methyiphenyl)piperazine with 4-tetrahydropyranone using a procedure analogous that set forth in Example 68. The crude product was purified by silica gel flash column chromatography using 95:5:0.5 chloroform: methanol: NH40H as eluant.
The title compound was obtained as a white foam by evaporation under pressure from ethyl acetate in 90% yield.
Analysis: C29H46N405S, 0.45 ethyl acetate calc. C, 61.40; H, 8.30; N, 9.30 found C, 61.03; 8.13; N, 9.54 TLC: Rf 0.30 (95-3:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.76 min, purity 98% FAB MS: m/z =563 H+) WO 95/02587 WO 9502587PCT/US94/07769 189 EXAMPLE 138 I -((7,7-dimethyl-2-endo-(28-(, 1, -dioxo-4-tetrahydrothiopyranyl)amino-3-hydroxypropionamido)-bicyclo(2.2. 1 )heptan- 1 -yI)methane- I fonyVI)-4- (2-methyl phenv lp1i pe razi ne
OH
3
HNN
0 2 S N"t
O
H O The title compound was prepared by reductive alkylation of 1 -dimethyl -2-endo- (2S -amino- 3 -hydrox ypropi onami do) -bicyc lo 20(2.2.1 )heptan-1I-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine with 4-tetrahydrothiopyranone followed by oxidation to the sulfone using procedures analogous those set forth in Example 109 and Example 1 The crude product was purified by silica gel flash column chromatography using 95:5:0.5 chloroform: methanol:NH4OH as eluant.
title compound was obtained as a white foam by evaporation under reduced pressure from chloroform.
Analysis: C29H46N406S2, 1.25 calc. C, 54.99; H, 7.72; N, 8.85 found C, 55.01; H, 7.99; N, 8.76 Rf 0.35 (95:5:0.5 CHCI3:MeOH:N}140H) HPLC (method retention time 8.88 min, purity 99% FAB MS: mlz= 611 (M WO 95/02587 PCTIUS94/07769 190- EXAMPLE 139 1 -dimethyl -2-endo- (2S -amino -3 r-hydroxybutyramido)bi cyc Io 2. 1 )hep tan I1 -yl)methanesulIfony l)-4 -(2-methylphenyl)y
CH
3 HNT0
H
2 N
CH
3 The title compound was prepared from 1-((7,7-dimethyl-2endo -amino -bicycl o(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine and Boc-L-threonine followed by TFA Ndeprotection. using procedures analogous to those set forth in Example 71 and Example 72. The crude product was purified by silica gel flash -clumn chromatography using 95:5:0.5 CHCI3:MeOH:N}140H as eluant.
The trifluoroacetate salt of the title compound was obtained as a white powder by lyophilization. from H20:CH3CN containing 0. 1% by volume of TFA.
Analysis: C25H4oN404.S, 1.75 TFA, 0. 1 caic. C, 49.32; H, 6.09; N, 8.07 found C, 49.35; H, 6.01; N, 7.93 TLC: Rf 0. 15 (95:5:0.5 CHCl3:MeOH:N1-40H) HPLC (method retention time 8.51 mmi, purity 99+% FAB MS: m/z= 493 (M WO 95102587 WO 9502587PCT/US94/07769 191 EXAMPLE 140 1 -dimethyl-2-endo-(2S-(4-piperidinyl)amino-3S-hydroxybutyramido)-bicyclo(2.2. 1 )heptan- I -yl)methanesulfonyl)-4-(2-methylphenyl)pip1erazine
OH
3
N-
HNT 0 HND N O H OH The title compound was prepared by reductive alkylation of 1 -dimethyl -2-endo-(2S -amino -3 S -hydrox ybuty ramido)-bicyclo- (2.2.1 )heptan- 1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine with I -te rt-buty lox ycarbony 1-4-piperi dino ne followed by TFA Ndeprotection using procedures analogous to those set forth in Example 129 and Example 140. The crude product was purified by preparative reverse phase HPLC using a water-acetonitrile gradient containing 0.1 by volume of TFA. The trifluoro acetate of the title compound was obtained as a white lyophilized powder in 80% yield.
Analysis: C30H49N504S, 2.5 TFA, 0.2 caic. C, 46.87; H, 6.24; N, 7.81 found C, 46.88; H, 6.01; N, 8.00 TLC: Rf 0.09 (90: 10:1 CHOl3: MeOH:NH4OH) HPLC (method retention time 8. 10 min, purity 99+% FAB MS: m/z= 576 (M WO 95/02587 PTU9/76 icr/US94/07769 192 EXAMPLE 141 1 -dimethyl -2-endo -(2S -tetrahydropyranyl)amino 3S-hydroxy- -bicyclo(2.2. 1 )heptan- Il-yI )methanesulfonyl)-4-(2-methylp2henvl)2iperazine
OH
3 0 0 HN, 0 01 N OH
H
CH
3 The title compound was prepared by reductive alkylation of 1 ,7-dimethyl-2-endo- (2S -amino -3 S-hydroxybutyramnido)-bicyc lo- (2.2.1 )heptan-1I-yl)methanesulfonyl )-4-(2-metahylphenyl)piperazine with 4-tetrahydropyranone using a procedure analogous that set forth in Example 104. The crude product was purified by silica gel flash column chromatography using 95:5:0.5 chloroformn:methanol :NH4OH as eluant. The title compound was obtained as a white foam by evaporation under reduced pressure from chloroform in 90% yield.
Analysis: C30H48N405S, 0.35 CHC13 caic. C, 58.92; H, 7.88; N, 9.06 found C, 59.07; H, 7.87; N, 9.13 TLC: Rf 0.44 (95:5:0.5 CHCI3:MeOH:NH4OH) HPLC (method retention time 8.96 min, purity 99% FAB MS: mlz= 577 (M WO 95/02587 WO 9502587PCT/US94/07769 193 EXAMPLE 142 1 ,7-dimethyl-2-endo-(2S-(4-ethoxycarbonyl)cyclohexylamino-4- (methylsulfonyl)butyramido)-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine
OH
3 H N H N H -a5-C 2
CH
2
CH
3
SO
2 C H 3 The title compound was prepared by reductive alkylation of 1 ,7-dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)butyramido)bicyclo(2.2. 1)heptan- 1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine with 4-ethoxycarbonylcyclohexanone using a procedure analogous that set forth in Example 68. The crude product was purified by silica gel flash column chromatography using 2:1 ethyl acetate:hexane as eluant. Two isomers of the title compound differing in configuration at the point of attachment of the ethoxycarbonyl substituent were obtained as a white foams.
Isomer Number I Analysis: C35H56N407S2, 1.55 caic. C, 57.86; H, 8.26; N, 7.39 found C, 57.85; H, 7.95; N, 7.62 TLC: Rf 0.13 (2:1 ethyl acetate:hexane) HPLC (method retention time 10.24 min, purity 99% FAB MS: m/z= 709 H+) Isomer Number 2 WO 95/02587 WO 9502587PCT/US94/07769 194- Analysis: C35H56N407S2, 0.2 ethyl acetate, 0.9 CH2CI2 caic. C, 54.89; H, 7.46; N, 6.98 found C, 54.95; H, 7.5 1; N, 7.00 TLC: Rf 0.26 (2:1 ethyl acetate:hexane) HPLC (method retention time 10.27 min, purity 99% FAB MS: m/z =709 (M EXAMPLE 143 1 -dimethyl-2-endo-(2S-(4-carboxy)cyclohexylamino-4-(methyl sulfonyl)butyramnidz)-bicyclo(2.2. 1 )heptan- 1 -yl)methanesulf-onyl)-4- (2-methvlphenvl )pip~erazine CHS3CH cotinn 2H N-aH( L Atrterato a ben0tireH a a pH solTonan te opouduc was petrced inobyl sacetfiate.n ofthe solvntas reoe une reduc m.Afe presrectiongivethen stited opot as a foam.
WO 95/02587 WO 9502587PCT/US94/07769 195 Analysis: C33H52N407S2, 0.55 ethyl acetate, 0.85 CH2C12 caic. C, 54.0 1; H, 7.3 1; N, 6.99 found C, 54.12; H, 7.18; N, 6,99 TLC: Rf 0.42 (90:10:0.5 CHC13:MeOH:HOAc) HPL-C (method retention time 9.06 min, purity 99% FAB MS: m/z =781 (M +1H+) EXAMPLE 144 1 -((7,7-dimethyl-4-(methylsulfonyl)-butyrarnido)-bicyclo(2.2. 1)heptan- 1 -vi)methauiesulfonvl )-4-(2-methvlphenflpiperazine
OH
3 6 200 S0 2 0H 3 The title compound was prepared by saponification of the Rf isomer from Example 106. 1-((7,7-Dimethyl-2-endo-(2S-(4- 25ethoxycarbonyl)cyclohexylamino-4-(methy lsu lfonyl)butyramido)bicyclo(2.2. 1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methylphenyl)piperazine (50 mg; 0.071 mmol) was dissolved in THF (2 mE) containing 2 N NaOH (1 mL). After the reaction had been stirred at temperature for 2 days, aqueous citric acid was added to obtain a pH 3 solution and the product was extracted into ethyl acetate. The solvent was removed under reduced pressure to give the title compound as a foam.
WO 95/02587 PCT/US94/07769 196- Analysis: C33H52N407S2, 0.65 ethyl acetate, 0.95 CHC13 calc. C, 53.60; H, 7.27; N, 6.84 found C, 53.64; H, 7.15; N, 6.85 TLC: Rf 0.44 (90:10:0.5 CHCl3:MeOH:HOAc) HPLC (method retention time 9.39 min, purity 99% FAB MS: m/z 781 (M H+)
TABLE
In addition to those compounds specifically exemplified above, additional compounds of the present invention are set forth in tabular form below. These compounds are synthesized by use of the synthetic routes and methods described in the above Schemes and Examples and variations thereof well known to those of ordinary skill in the art, and not requiring undue experimentation. All variables listed in the Tables below are with reference to the following generic structure: R2
R
3
R
1 2 (CH 2 R R 8
R
4
R
5 N N'
X"
R
6
(CH
2
R
3/al
R
9 Variable Variable In this generic structure, all values for V are for a substituted carbon atom which is to be understood to be in the 2 position of the camphor ring; therefore, in the following table, said substituted WO 95/02587 PCT/US94/07769 197 carbon atom generally only shows two valence bonds, the other two valence bonds being understood to be part of the camphor ring. When said substituted carbon atom only shows one valence bond, it is to be understood that a double bond is present between the 2 and 3 positions of the camphor ring.
TABLE OF SUBSTITUENTS REPRESENTED BY "V" V C N,OH H 0 CNC CO C Ha
H
0O
/OHO
C NC CH 3
H
COH
H 0O C0 N
OC
0 WO 95/02587 WO 9502587PCT/US94/07769 198 TABLE (Continued) 0 /OH 1 OH 3
H
c N
NH
H
0 Ok
H
3
CH
3
OH
3
OH
3 WO 95/02587 WO 9502587PCT/US94/07769 199 TABLE (Continued) ,OH 0
HNH
H
H N-r N 0 0 N ,OH 0 H c N N 'Y0 x H 3
HN
,OH 0 -4NH ,OH N0 N~0
OH
3 H HN_, WO 95/02587 WO 95/2587 cTIUS94/07769 200 TABLE (Continued)
OH
3 ,O0H 0 c
H\
H
N-N
CH3
H
,OH
C
\r-"N OH 3
H
0
C-OH
0 WO 95/02587 WO 9502587PCTIUS94/07769 201 TABLE (Continued) ~,OH 0
OH
3 Hlo ,OH 0 H c N N
OH
3 H0 0 11 -C OH
OH
3
H
,OH 0 N-N N
~N
OH1 3
H
C, OTh0I---CH,3 0
H
/0H 0 WO 95/02587 WO 9502587PCT/US94/07769 202 TABLE (Continued)
<OCH
3 0 01 ,OH 0
-N
N
N
OH
3
H
0 CH3 0 H, 3 C OH 3 0 0 ,,OH 0
SO
3
N
CH
3
H
/.OH 0 0 K Nk OH OH 3
H
WO 95/02587 PCT/US94/07769 203 TABLE (Continued) ,.OH 0
OH
3
H
HO' 0 0 O FF .,HO 0 CH Os N ,N-N 3 N 0 O N N-OH 3 O cH 3 Oc
N
,-r0 0 0
N
O OH 3 WO 95/02587 PTU9/76 PCT/US94/07769 204 TABLE (Continuied) 0 /OH 0 C, 0 CH 2 CH 3
OH
3 .OH 0 N, C.H 2
CH
3
OH
3 H0 0OH
CH
3 0 H0 N N 0, ,H 3 H0
OH
3 0 N 0 H 0
,,OH
C Y
OH
3 WNO 95/02587 PTU9/76 PCT/US94/07769 205 TABLE (Continued) 0
H
NH
2 /HO0 ,N
NH
2
H
H
o, N o
N
H
Cs 0 N 0 0
OH
WO 95/02587 WO 9502587PCT/US94/07769 206 TABLE (Continued)
OH
OH 0 0 C N)L O-Na+
YH
CH
3
OH
,H O0
CN
H
0 'J o HO0 0 c IsI N N 11CH 3 H HO0 ,H O0
CN
H
O N==r N. NH O H 0 c 1CH 3
CH
3 H 0
OHN
H N-- NN 0 Y 1 0 SCH 3 WO 95/02587 WO 95/2587 CT/US94/07769 207 Additional examples of species covered by this invention include the following non-limiting list: 'so 2 WO 95/02587 PCT/US94/07769 208
CH
3
OH
3
ON
WO 95/02587 PICI/US94/07769 209 WO 95/02587 PCT/US94/07769 -210- EXAMPLE 145 RADIOGLIGAND BINDING ASSAYS The high affinity binding of 3 H] Oxytocin (OT)([tyrosyl, 3,5-[ 3 H]OT; 30-60 Ci/mmol; New England Nuclear. Boston, MA) to uterine OT receptors was based on an assay (Fuchs, A-R; Fuchs, F; Soloff, MS. 1985 J. Clin. Endocrinol. Metab. 60:37) using a crude membrane preparation of uteri taken from diethylstilbestrol dipropionate (DES)-treated (0.3 mg/kg, ip; 18-24) rats. Competition studies were conducted at equilibrium (60 minutes; 22 0 C) using 1 nM[ 3 H]OT in the following assay buffer: 50 mM Tris-HCI, 5 mM MgCl2, and 0.1% BSA, pH 7.4. Nonspecific binding (10% of the total binding) was determined using 1 mM unlabeled OT and the binding reaction was terminated by filtration through glass fiber filters using a cell harvester (model 7019, Skatron, Inc., Sterling, VA). IC50 (the concentration of tested compound that inhibits 50% of OT) was reported, unless otherwise noted.
The measurement of 3 H]Vasopressin (AVP) ([phenylalanyl-3,4,5- 3 H]AVP; 80-90 Ci/mmol; New England Nuclear)binding to a crude membrane preparation of male rat liver (AVP-VI sites) or kidney medulla (AVP-V2 sites) was determined according to the method of Butlen, et al., (Butlen, D; Guillon, G; Rajerison, Jard, S; Sawyer, Manning, M. 1978 Mol Pharmacol. 14:1006).
Competition assays were conducted at equilibrium minutes at 30 0 C) using 1 nM 3 H]AVP (liver) or 2 nM 3
H]AVP
(kidney) in the following assay buffer: 100 mM Tris-HCl, 5 mM MgCI2, 0.1% BSA, 50 mM phenylmethylsulfonylfluoride, and mg/ml bacitracin, pH 8.0. Nonspecific binding (5-10% of the total binding) was determined using 10 mM unlabeled AVP, and the binding reaction was terminated by filtration as described above for the 3
H]OT
binding assay.
Ki values were obtained for each compound from three to six separate determinations of the IC50 values (Ki IC50/1 c/Kd) WO 95/02587 WO 9502587PCTI/US94/07769 -211 (Cheng, Y-C; Prusoff, 1973 Biochem Pharmnacol 22:3099) using Kd values obtained from a saturation binding assay: 3 H]OT (uterus), 0.7 nM; Ii 3 H]AVP (liver), 0.4 n.M; 3 H] (kidney), 1.4 nM.
1.C50 1 145; 155 nM 2 800 nM 3 150OnM 4 53% inhib. at1000nM 5 27% inhib. atl1000nM 6 82 nM 7 830; 16000 nM 8 4.3 9 6.5 nM 10 75% inhib. atl1000nM 11 1100nM 12 15.3nM 13 33.3 nM 14 5 15 16 27 nM 17 16nrM 18 120OnM 19 160OnM 20 3.6 nM 37 1,000nM 38 150OnM 39 180OnM 34 nM 41 100 nM 42 10 nM 43 8 nM 44 18 nM 5 nM WO 95/02587 PCT/US94/07769 -212- 46 48% inhibition at 100 nM 47 54 nM 48 23% inhibition at 100 nM 49 1,100 nM 44% inhibition at 1,000 nM 51 64% inhibitiun at 1,000 nM 52 36% inhibition at 100 nM 53 75% inhibition at 1,000 nM 54 31% inhibition at 1,000 nM 55 72% inhibition at 1,000 nM 56 38% inhibition at 1,000 nM 57 78% inhibition at 1,000 nM 58 120 nM 59 260 nM 34% inhibition at 100 nM 61 35 nM 62 37% inhibition at 100 nM 63 35% inhibition at 100 nM 64 78% inhibition at 1,000 nM 65 16% inhibition at 10,000 nM 16% inhibition at 10,000 nM 66 5% inhibition at 1,000 nM 67 37% inhibition at 1,000 nM 68 460 nM 69 70 91% inhibition at 100 nM 71 7.7 nM 72 1.2 nM 73 5.4 nM 74 54% inhibition at 1,000 nM 75 35% inhibition at 1,000 nM 76 6.3 nM 77 9.2 nM 78 110 nM 79 26 nM WO 95/02587 PCTIUS94/07769 -213 12 nM 81 20 nM 82 15 nM 83 30 nM 84 25 nM 66% inhibition at 100 nM 86 38 nM 87 66% inhibition at 100 nM 88 28 nM 89 14 nM 30 nM 91 54 nM 92 66% inhibition at 100 nM 94 56 nM While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred dosages as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for prevention of preterm labor, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
Claims (15)
1. A cornpound of the formula R R 2/c) (C0H 2 6m7 R -R' z R1 wherein a is a single or double bond; W is C or 0, provided that when W is 0, then R 7 and R 8 are not present; X is CH or N; Y is carbonyl, sulfonyl or -CON1-I-; Z is an optional substituent that, when present, is substituted or unsubstituted alkyl where said substituent is carboxyl; WO 95/02587 PCT/U7 ./07769 R1 is R 2 is hydrogen, unsubstituted or substituted alkyl where said substituent is halogen, halogen or alkoxy; hydrogen, unsubstituted or substituted alkyl where said substituent is halogen, halogen or alkoxy; R 5 and R 6 :1) (2) (3) (4) R 7 and R 8 (1) (2) are each independently selected from hydrogen, alkyl, phenylalkyl or oxo; are each independently selected from hydrogen, or alkyl, or R 7 and R 8 together with W, when W is carbon, form a C3-6 carbocyclic ring; R 9 and R10 are together joined to form cyclic epoxide,whereby the R 9 and R 10 substituents are on the same carbon or on adjacent carbon atoms; or R 9 and R 10 (1) (2) are each independently selected from hydrogen, hydroxyl, WO 95/02587 PCT/US94/07769 -216 halogen, oximido, methyl, carboxyl, carboxyalkyl, oxo, unsubstituted or substituted alkoxycarbonyl where said substituent is selected from pyridyl or piperidinyl, alkylcarbonyloxy, (11) alkylcarbonyloxyalkyl, (12) alkoxycarbonylalkoxy, (13) cyanoalkyl, (14) hydroxyalkyl, trihaloalkylsulfonyloxo, or (16) unsubstituted or substituted amino where said substituent is one or more of alkyl, carboxyalkyl or alkoxycarbonylalkyl; R 11 is hydrogen, oxo, -N(R 12 )-CO-R 1 3 or -CO-N(R 1 4 )-R 1 5 R 12 is hydrogen, alkoxy, unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, hydroxyl, alkoxyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl, alkoxycarbonyl or alkoxycarbonylamino; WO 95/02581 PCT/US94/07769 -217- R 13 is hydrogen, alkoxyl, aralkoxyl, carboxyl, alkoxycarbonyl, alkoxycarbonylamino, unsubstituted or substituted cycloalkyl, wherein said substituent is carboxyl, unsubstituted Jr substituted phenyl wherein said substituent is one or more of carboxyl, carboxyalkyl or SO3H, unsubstituted or substituted amino, wherein said substituent is unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, alkylsulfonyl or unsubstituted membered heterocyclic rings having 1 or 2 heteroatoms, where said heteroatom is N, unsubstituted or substituted heterocyclic rings selected from the group consisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetra- hydropyranyl, tetranydrothiopyranyl, 1 -oxotetrahydro- thiopyranyl and 1,1-dioxotetrahydrothiopyranyl and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, alkylcarbonyl, carboxyl, carboxyalkyl, carboxyaralkyl, aralkyl, aralkylcarbonyl, aralkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyi, aminoalkylcarbonyl, cyano, alkylsulfonyl, alkoxycarbonyl- aminoalkylcarbonyl, oxo or unsubstituted or substituted amino wherein said substituent is one or more of alkyl, carboxylalkyl, alkoxycarbonyl or alkoxycarbonylalkyl or (11) unsubstituted or substituted alkyl, wherein said substituent is one or more of hydroxyl, alkoxy, carboxyl, phenyl, hydroxyphenyl, alkylphenyl, carboxyalkylphenyl, cyano, WO 95/02587 PCT/US94/07769 -218- alkylsulfonyl, acetamidino, formamidino, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, thio, alkylthio, alkoxycarbonyl, alkoxycarbonylalkyl, Het, or unsubstituted or substituted amino, wherein said -bstituent is one or more of alkyl, deuterated alkyl, piperidinyl, Cyc, pyridinyl, morpholinyl, tetrahydro- pyranyl, tetrahydrothiapyranyl, tetrahydrothiapy,:anyl S- oxide, alkoxycarbonylpiperidinyl, cyano, cyanoalkyl, hydroxyalkyl, haloalkyl, dialkyl, alkylcarbonyl, carboxyl, alkylsulfonyl, carboxyalkyl, alkoxycarbonyl, alkoxy- carbonylalkyl, aralkoxycarbonyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, phenalkyl or unsubstituted or substituted alkylcarbonyl, where said substituent is a 5-membered heterocyclic ring having 1 or 2 heteroatoms and where said hetero atom is N, Cyc is defined as unsubstituted or substituted cycloalkyl wherein said substituent is alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolanyl and Het is defined as heterocyclic rings selected from the group consisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothiopyranyl and 1,1-dioxotetrahydrothiopyranyl; and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, amino, carboxyl, carboxyalkyl, aralkyl, carboxyaralkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl, aralkyl- carbonyl, aralkoxyalkyl, phenyl, aralkoxycarbonyl, oxo, S03H, or unsubstituted or substituted amino wherein said substituent is alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl; WO 95/02587 PCT/US94/07769 -219 R 14 and R 15 are each independently selected from hydrogen, unsubstituted or substituted alkyl where said substituent is one or more of hydrogen, carboxyl, amino, dialkylamino, aminoalkylamino, aminocarbonyl, hydroxyl, alkoxyl, alkylthio, thioalkyl, alkylsulfinyl, aikylsulfonyl, phenyl- alkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenalkyl or unsubstituted 5-membered saturated heterocyclic rings having 1 or 2 hetero atoms wherein said hetero atom is N or unsubstituted or substituted heterocyclic rings selected from the group consisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetrahydro- pyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothio- pyranyl and 1,1-dioxotetrahydrothiopyranyl and wherein said substituent is one or more of alkyl, oxo, carboxyl, phenylalkyl, carboxyphenylalkyl or alkoxycarbonyl; and m and n are integers of from 0 to 1; with the proviso that the bridging methylene moiety -(CH2)n-, when n is equal to 1, or the moiety Y, when n is equal to 0, shall not ber. bonded to the camphor ring at either bridgehead position 3 or bridgehead position 6 unless Y is -CONH-; and the pharmaceutically acceptable salts thereof.
2. The compound of Claim 1 of the formula I WO 95/02587 PCT/US94/07769 -220- R 7 ,jL ,R8 R 10 wherein Y is carbonyl or sulfonyl; R 7 and R 8 (1) are each independently selected from alkyl, or R 7 and R 8 together with W, when W is carbon, form a C3-6 carbocyclic ring; R 9 and R 10 are each independently selected from hydrogen, hydroxyl, oximido, methyl, carboxyl, carboxyalkyl, unsubstituted or substituted alkoxycarbonyl where said substituent is selected from pyridyl or piperidinyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, cyanoalkyl, (11) hydroxyalkyl or e WO 95/02587 PCT/US94/07769 -221 (12) unsubstituted or substituted amino where said substituent is one or more of alkyl, carboxyalkyl or alkoxycarbonylalkyl; and R 12 is (1) (2) hydrogen or unsubstituted or substituted alkyl where said substituent is one or more of carboxyl, hydroxyl, alkoxyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl.
3. The compound of Claim 2 of the formula wherein R 9 and R 1 0 (1) (2) (3) (4) (6) (7) (8) (9) (11) are each independently selected from hydrogen, hydroxyl, oximido, methyl, carboxyl, carboxyalkyl, unsubstituted or substituted alkoxycarbonyl where said substituent is selected from pyridyl or piperidinyl, alkylcarbonyloxyalkyl, cyanoalkyl, hydroxyalkyl or unsubstituted amino; I WO 95/02587 WO 9502587PCT/US94/07769 222 R 13 is alkoxyl, unsubstituted or substituted heterocyclic rings selected from the group consisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl, thiazinyl, azepinyl, tetrahydro- pyranyl, tetrahydrothiopyranyl, 1 -oxotetrahydrothlo- pyranyl and 1,1-dioxotetrahydrothiopyranyl and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, alkylcarbonyl, carboxyl, carboxyalkyl, carboxyaralkyl, aralkyl, araikylcarbonyl, aralkoxy- carbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, amino- alkylcarbonyl, cyano, alkylsulfonyl, alkoxycarbony] amino- alkylcarbonyl, oxo or unsubstituted or substituted amino wherein said substituent is one or more of alkyl, carboxylalkyl, alkoxycarbonyl or alkoxycarbonylalkyl or unsubstituted or substituted alkyl, wherein said substituent is one or more of hydroxyl, alkoxy, carboxyl, phenyl, hydroxyphenyl, alkyiphenyl, carboxyalkyiphenyl, cyano, alkylsulfonyl, acetamidino, formamidino, aminocarbonyl, alkylaminocarbonyl, aralkyl, aralkoxycarbonyl, halogen, thio, alk) thio, alkoxycarbonyl, alkoxycarbonylalkyl, Het, or unsub- "Iuted or substituted amino, wherein said substituent is one or more of alkyl, deuterated alkyl, piperidinyl, Cyc, pyridinyl, mor-pholinyY tetrahydro- pyranyl, tetrahydrothiapyranyl, tetrahydrothiapyranyl S- oxide, alkoxycarbonylpiperidinyl, cyano, cyanoalkyl, hydroxyalkyl, haloalkyl, dialkyl, alkylcarbonyl, carboxyl, alkylsulfonyl, carboxyalkyl, a ikoxycarbonyl, alkoxy- carbonylalkyl, aralkoxycarbonyl, arninoatkyl, amino- carbonyl, amino carbonylIatkyl1, alkylaminocarbonyl, phenalkyl or unsubstituted or substituted alkylcarbonyl, where said substituent is a 5-membered heterocyclic ring WO 95/02587 PCT/IJS9407769 -223 having I or 2 heteroatoms and where said hetero atom is N, Cyc is defined as unsubstituted or substituted cycloalkyl wherein said substituent is alkoxycarbonyl, carboxyl, hydroxyl, oxo or spiro-dioxolanyl and Het is defined as heterocyclic rings selected from the group consisting of: pyrrolidinyl, tetrahydroimidazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, piperidinyl, piperizinyl, pyridinyl, quinuclidinyl, morpholinyl. thiazinyl, azepinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxotetrahydrothiopyranyl and I ,1-dioxotetrahydrothiopyranyl; and wherein said substituent for any of said heterocyclic rings are one or more of alkyl, amino, carboxyl, carboxyalkyl, aralkyl, carboxyaralkyl, alkoxycarbonyl, halogen substituted alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl, aralkylcarbonyl, aralkoxyalkyl, phenyl, araikoxycarbonyl, oxo, S03H, or unsubstituted or substituted amino wherein said substituent is alkyl, carboxyl, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl; 15 are each independently selected from hydrogen or unsubstituted or substituted alkyl where said substituent is one or more of hydrogen, carboxyl, amino, dialkylamino, aminoalkylamino, aminocarbonyl, hydroxyl, alkoxyl, alkylthio, thioalkyl, alkYlsulfinyl, alkylsulfonyl, phenyl- alkoxycarbonyl, alkoxycarbonyl, indolyl, phenalkyl, hydroxyphenaikyl or unsubstituted 5-membered saturated heterocyclic rings having 1 or 2 hetero atoms wherein said hetero atom is N. R 14 and R (1) (2) WO 95/02587 PCT/US94/07769 -224
4. The compound of Claim 3 of the formula RT R 8 R 11 9 N N CH 3 wherein R1 2 is hydrogen; and R 14 and R 15 are each independently selected from hydrogen or unsubstituted or substituted alkyl where said substituent is one or more of dialkylamino, hydroxyl, alkylthio or thioalkyl. The compound of Claim 4, wherein Y is carbonyl; R 1 1 is -N(R 12 )-CO-R 13 or -CO-N(R 14 )-R 1 5 and 2 5 R 13 is hydrogen, alkoxyl, unsubstituted or substituted pyrrolidinyl wherein said substituent is alkoxycarbonylalkyl or (11) unsubstituted or substituted alkyl, wherein said substituent is one or more of hydroxyl, alkylsulfonyl, imidazolyl, or unsubstituted or substituted amino, wherein said substituent is one or more of tetrahydropyranyl or alkoxycarbonyl. WO 95/02587 WO 9502587PCI'/US94/07769 225
6. The compound of Claim 5 selected from the group consisting of 0 -S CH. 0 0 H 2 N 13 and 226
7. An oxytocin antagonistic derivative of piperazinylcamphor, substantially as hereinbefore described with reference to any one of the Examples.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound as claimed in any one of claims 1 to 7.
9. A method of antagonizing the binding of oxytocin to its receptor binding site in a mammalian biologic system, comprising the step of introducing a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of claim 8. A method of preventing preterm labor in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of claim 8.
11. A method of stopping labor prior to cesarian delivery in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of 15 claim 8.
12. A method for treating dysmenorrhea in a mammal in need thereof, comprising S" the step of administering to said mammal a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of claim 8.
13. A method of antagonizing vasopressin from binding to its receptor site in a mammal, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of claim 8. i 14. A method of inducing vasodilation in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of claim 8.
15. A method of treating hypertension in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of claim 8.
16. A method of inducing diuresis in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of claim 8.
17. A method of inhibiting platelet agglutination in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of any one of claims 1 to 7 or of the composition of claim 8. Dated 12 January, 1996 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON IN \I.BFP26409 SAK INTERNATIONAL SEARCH REPORT nternational application No. PCT/US94/07769 A. CLASSIFICATION OF SUBJECT MATTER :Please See Extra Sheet. US CL :Please See Extra Sheet. According to International Patent Classification (IPC) or to both national classification and IPC I B. FIELDS SEARCHED L Minimum documentation searched (classification system followed by classification symbols) U.S. Please See Extra Sheet. Documentation searched other than minimum documentation to the extent that such documents arc included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CAS ONLINE STRUCTURE SEARCH C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Y EP, A, 0,532,097 (BACK et al.) 17 March 1993, see entire 1-17 document. Y EP, A, 0,533,240 (ERB et al.) 24 March 1993, see entire 1-17 document. Y EP, A, 0,533,241 (ERB et al.) 24 March 1993, see entire 1-17 document. Y EP, A, 0,533,242 (BOCK et al.) 24 March 1993, see entire 1-17 document. Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: Later document publishd aiter the international iling date or pnonty date and not in connict with the application but cited to underntand the "A documentdefming the eneral state of the art which is not conidered principle or heoy underlying the nvent i n to to be of particular relevance earlier document publihad on or afler the international mli date document of particular relevance; the clauned invention cauol be considered novel or cannot be conuidered to involve an inventive ltep document which may throw doubts on priority claim(s) or which in when the document u taken alone cited to establish the publication date of another citaton or other special reason (s speciied) document of paricular relevance, the claiuned uventon cannot be conilered ino involve an mvenve step when the documentl *0 document refering to an oral discloure, use, exhibition or other combmied with one or more other such documents, such combination m C ns bcing obvious to a person skilled m the an documentpubtished prior to the International film date but later than document member of the same patent fanily the priority date claimed Date of the actual completion of the international search Date of mailing of the international search repo 03 OCTOBER 1994 2 1 OCT19 Name and mailing address of the ISA/US Authorized officer Commissioner of Patents and Trademarks Box PCT Washington, D.C. 20231 Emily Bernhardt ach Facsimile No. (703) 305-3230 Telephone No (703) 308-1235 Form PCT/ISA/210 (second sheet)(July 1992)* IN4TERNATIONAL SEARCH REPORT Interational application No. PCT/US94/07769 A. CLASSIFICATION OF SUBJECT MATTER' IPC C07D 295/26, 295/205, 401/04, 401/12, 403/12, 405/12, 409/12, 413/12, 417/12, 453/02; A61K 31/495. A. CLASSIFICATION OF SUBJECT MATITER: US CL 544/53, 54, 121, 230, 360, 362, 364, 365, 370, 372. 373, 374, 376, 379, 383, 384, 385, 391; 540/598; 5 14/212,
226.8, 227.2, 235.8, 252, 253, 254, 255. B. FIELDS SEARCHED Minimum documentation searched Classification System: U.S. 544/53, 54, 121, 230, 360, 362, 364, 365, 370, 372, 373, 374, 376, 379, 383, 384, 385, 391; 540/598; 514/212, 226.8, 227.2, 235.8, 252-2.55. Form PCTIISA/210 (extra sheet)(July 1992)*
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9350293A | 1993-07-16 | 1993-07-16 | |
| US093502 | 1993-07-16 | ||
| PCT/US1994/007769 WO1995002587A1 (en) | 1993-07-16 | 1994-07-11 | Substituted piperazinylcamphor derivatives as oxytocin antagonists |
Publications (2)
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|---|---|
| AU7329294A AU7329294A (en) | 1995-02-13 |
| AU675730B2 true AU675730B2 (en) | 1997-02-13 |
Family
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|---|---|---|---|
| AU73292/94A Ceased AU675730B2 (en) | 1993-07-16 | 1994-07-11 | Substituted piperazinylcamphor derivatives as oxytocin antagonists |
Country Status (6)
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|---|---|
| US (1) | US5686454A (en) |
| EP (1) | EP0708765A4 (en) |
| JP (1) | JPH09500133A (en) |
| AU (1) | AU675730B2 (en) |
| CA (1) | CA2166974A1 (en) |
| WO (1) | WO1995002587A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5464788A (en) * | 1994-03-24 | 1995-11-07 | Merck & Co., Inc. | Tocolytic oxytocin receptor antagonists |
| US20020128208A1 (en) * | 2000-12-15 | 2002-09-12 | Snyder James P. | Nonpeptide agonists and antagonists of vasopressin receptors |
| AR047759A1 (en) * | 2003-09-26 | 2006-02-22 | Vertex Pharma | FENIL DERIVATIVES - PIPERAZINE AS MODULATORS OF MUSCARNIC RECEPTORS |
| WO2010134014A1 (en) | 2009-05-18 | 2010-11-25 | Actelion Pharmaceuticals Ltd | Bridged spiro [2.4] heptane derivatives as alx receptor and/or fprl2 agonists |
| ES2553635T3 (en) | 2010-11-17 | 2015-12-10 | Actelion Pharmaceuticals Ltd. | Derivatives of spiro [2.4] bridged heptane ester |
| MA37618B1 (en) | 2012-05-16 | 2017-08-31 | Actelion Pharmaceuticals Ltd | Fluor [2.4] heptane fluorinated bridged derivatives as alx receptor agonists |
| JP6101788B2 (en) * | 2012-05-16 | 2017-03-22 | アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ | 1- (p-Tolyl) cyclopropyl substituted bridged spiro [2.4] heptane derivatives as ALX receptor agonists |
| AR096686A1 (en) | 2013-06-25 | 2016-01-27 | Actelion Pharmaceuticals Ltd | DERIVATIVES OF ESPIRO [2.4] HEPTANO BRIDGES SUBSTITUTED WITH DIFLUOROETIL-OXAZOL AS AGONISTS OF THE ALX RECEIVER |
| JP6330038B2 (en) * | 2013-07-18 | 2018-05-23 | イドーシア ファーマシューティカルズ リミテッドＩｄｏｒｓｉａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ | Piperazine-substituted cross-linked spiro [2.4] heptane derivatives as ALX receptor agonists |
| WO2019090090A1 (en) * | 2017-11-02 | 2019-05-09 | Calico Life Sciences Llc | Modulators of the integrated stress pathway |
| US11939320B2 (en) | 2017-11-02 | 2024-03-26 | Abbvie Inc. | Modulators of the integrated stress pathway |
| TWI771621B (en) | 2018-10-11 | 2022-07-21 | 美商嘉來克生命科學有限責任公司 | Prodrug modulators of the integrated stress pathway |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0533241A2 (en) * | 1991-09-16 | 1993-03-24 | Merck & Co. Inc. | Substituted alkyl derivatives of piperazinylcamphorsulfonyl oxytocin antagonists |
| EP0533242A2 (en) * | 1991-09-16 | 1993-03-24 | Merck & Co. Inc. | Substituted derivatives of piperazinylcamphorsulfonyl oxytocin antagonists |
| EP0533240A2 (en) * | 1991-09-16 | 1993-03-24 | Merck & Co. Inc. | Substituted amine derivatives of piperazinylcamphorsulfonyl oxytocin antagonists |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES374515A1 (en) * | 1969-12-12 | 1972-01-01 | Liade Sa Lab | Procedure for obtaining new compounds with cardiovascular actions. (Machine-translation by Google Translate, not legally binding) |
| ES432334A1 (en) * | 1974-11-27 | 1976-11-01 | Liade Sa Lab | 11 amidoarukiru 44 suruhoniruupiperajinkagobutsunoseizoho |
| US4147870A (en) * | 1976-05-19 | 1979-04-03 | Laboratorios Liade, S.A. | 1-Arylamidoethyl, 4-sulfonylpiperazines |
| US4087425A (en) * | 1976-08-12 | 1978-05-02 | Laboratorios Liade, S.A. | N,N-Disulfonylpiperazines |
| US4547505A (en) * | 1983-03-25 | 1985-10-15 | Degussa Aktiengesellschaft | N-Phenyl-N-'-cycloalkylalkanoylpiperazine useful as analgetics and process for its production |
| IT1228454B (en) * | 1989-02-22 | 1991-06-19 | Roussel Maestretti S P A Milan | DERIVATIVES OF 1-ARILSOLFONIL 2 PIPERIDONE, THEIR PREPARATION PROCEDURE AND THEIR USE AS DRUGS. |
| CA2037287A1 (en) * | 1990-03-02 | 1991-09-03 | Ben E. Evans | Spirocyclic oxytocin antagonists |
| US5091387A (en) * | 1990-03-02 | 1992-02-25 | Merck & Co., Inc. | Spirocyclic oxytocin antagonists |
| FR2665441B1 (en) * | 1990-07-31 | 1992-12-04 | Sanofi Sa | N-SULFONYL INDOLINE DERIVATIVES, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAME. |
| IL99957A0 (en) * | 1990-11-13 | 1992-08-18 | Merck & Co Inc | Piperidinylcamphorsulfonyl oxytocin antagonists and pharmaceutical compositions containing them |
| SK28794A3 (en) * | 1991-09-13 | 1995-07-11 | Merck & Co Inc | Piperazinyl(sulfonyl) amide derivatives of camphor as oxytocin antagonists |
| US5204349A (en) * | 1991-09-16 | 1993-04-20 | Merck & Co., Inc. | Amide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists |
| WO1994007496A1 (en) * | 1992-10-07 | 1994-04-14 | Merck & Co., Inc. | Tocolytic oxytocin receptor antagonists |
| US5464788A (en) * | 1994-03-24 | 1995-11-07 | Merck & Co., Inc. | Tocolytic oxytocin receptor antagonists |
-
1994
- 1994-07-11 EP EP94923424A patent/EP0708765A4/en not_active Withdrawn
- 1994-07-11 US US08/578,640 patent/US5686454A/en not_active Expired - Fee Related
- 1994-07-11 CA CA002166974A patent/CA2166974A1/en not_active Abandoned
- 1994-07-11 AU AU73292/94A patent/AU675730B2/en not_active Ceased
- 1994-07-11 WO PCT/US1994/007769 patent/WO1995002587A1/en not_active Application Discontinuation
- 1994-07-11 JP JP7504653A patent/JPH09500133A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0533241A2 (en) * | 1991-09-16 | 1993-03-24 | Merck & Co. Inc. | Substituted alkyl derivatives of piperazinylcamphorsulfonyl oxytocin antagonists |
| EP0533242A2 (en) * | 1991-09-16 | 1993-03-24 | Merck & Co. Inc. | Substituted derivatives of piperazinylcamphorsulfonyl oxytocin antagonists |
| EP0533240A2 (en) * | 1991-09-16 | 1993-03-24 | Merck & Co. Inc. | Substituted amine derivatives of piperazinylcamphorsulfonyl oxytocin antagonists |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995002587A1 (en) | 1995-01-26 |
| JPH09500133A (en) | 1997-01-07 |
| AU7329294A (en) | 1995-02-13 |
| EP0708765A4 (en) | 1996-06-26 |
| US5686454A (en) | 1997-11-11 |
| CA2166974A1 (en) | 1995-01-26 |
| EP0708765A1 (en) | 1996-05-01 |
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| Date | Code | Title | Description |
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| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |